U.S. patent number 10,610,103 [Application Number 16/543,338] was granted by the patent office on 2020-04-07 for transcutaneous analyte sensor.
This patent grant is currently assigned to DexCom, Inc.. The grantee listed for this patent is DexCom, Inc.. Invention is credited to Mark C. Brister, Paul V. Goode, Jr., Jacob S. Leach, John Nolting, Luis Pestana, Jack Pryor, Nelson Quintana, Vance Swanson, James Patrick Thrower.
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United States Patent |
10,610,103 |
Brister , et al. |
April 7, 2020 |
**Please see images for:
( Certificate of Correction ) ** |
Transcutaneous analyte sensor
Abstract
The present invention relates generally to systems and methods
for measuring an analyte in a host. More particularly, the present
invention relates to systems and methods for transcutaneous
measurement of glucose in a host.
Inventors: |
Brister; Mark C. (Encinitas,
CA), Pryor; Jack (Ladera Ranch, CA), Nolting; John
(Poway, CA), Leach; Jacob S. (San Diego, CA), Pestana;
Luis (San Diego, CA), Quintana; Nelson (San Diego,
CA), Swanson; Vance (San Diego, CA), Goode, Jr.; Paul
V. (Round Rock, TX), Thrower; James Patrick (Oakland,
NJ) |
Applicant: |
Name |
City |
State |
Country |
Type |
DexCom, Inc. |
San Diego |
CA |
US |
|
|
Assignee: |
DexCom, Inc. (San Diego,
CA)
|
Family
ID: |
40452384 |
Appl.
No.: |
16/543,338 |
Filed: |
August 16, 2019 |
Prior Publication Data
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Document
Identifier |
Publication Date |
|
US 20190365227 A1 |
Dec 5, 2019 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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16503017 |
Jul 3, 2019 |
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15586134 |
May 3, 2017 |
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14576103 |
Dec 18, 2014 |
9668682 |
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12869996 |
Aug 27, 2010 |
9451910 |
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11855101 |
Sep 13, 2007 |
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16543338 |
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16392521 |
Apr 23, 2019 |
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14590483 |
Jan 6, 2015 |
10314525 |
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13909962 |
Jun 4, 2013 |
9247900 |
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11360262 |
Feb 22, 2006 |
8615282 |
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16543338 |
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16133469 |
Sep 17, 2018 |
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15686650 |
Aug 25, 2017 |
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14144523 |
Dec 30, 2013 |
9775543 |
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12749139 |
Mar 29, 2010 |
8663109 |
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11157365 |
Jun 21, 2005 |
7905833 |
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16543338 |
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16179662 |
Nov 2, 2018 |
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15891201 |
Feb 7, 2018 |
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14293298 |
Jun 2, 2014 |
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13361820 |
Jan 30, 2012 |
8968198 |
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11360250 |
Feb 22, 2006 |
8133178 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B
5/0022 (20130101); A61B 5/6849 (20130101); A61B
5/742 (20130101); A61B 5/14532 (20130101); A61B
5/6848 (20130101); A61B 5/6832 (20130101); A61B
5/1411 (20130101); A61B 5/14507 (20130101); A61B
5/1473 (20130101); A61B 5/6833 (20130101); A61B
5/14546 (20130101); G16Z 99/00 (20190201); A61B
5/150534 (20130101); A61B 5/1486 (20130101); A61B
5/14865 (20130101); Y02A 90/22 (20180101); A61B
2562/08 (20130101); A61B 5/0002 (20130101); A61B
2560/0223 (20130101); A61B 5/150022 (20130101); A61B
2560/0214 (20130101); Y02A 90/26 (20180101); Y02A
90/10 (20180101) |
Current International
Class: |
A61B
5/00 (20060101); A61B 5/1486 (20060101); G16Z
99/00 (20190101); A61B 5/145 (20060101); A61B
5/15 (20060101); A61B 5/1473 (20060101) |
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|
Primary Examiner: Jang; Christian
Attorney, Agent or Firm: Knobbe, Martens, Olson & Bear,
LLP
Parent Case Text
INCORPORATION BY REFERENCE TO RELATED APPLICATIONS
Any and all priority claims identified in the Application Data
Sheet, or any correction thereto, are hereby incorporated by
reference under 37 CFR 1.57. This application is a continuation of
U.S. application Ser. No. 16/503,017, filed Jul. 3, 2019, which is
a continuation of U.S. application Ser. No. 15/586,134, filed May
3, 2017, which is a continuation of U.S. application Ser. No.
14/576,103, filed Dec. 18, 2014, now U.S. Pat. No. 9,668,682, which
is a continuation of U.S. application Ser. No. 12/869,996, filed
Aug. 27, 2010, now U.S. Pat. No. 9,451,910, which is a continuation
of U.S. application Ser. No. 11/855,101, filed Sep. 13, 2007, now
abandoned. This application is a continuation-in-part of U.S.
application Ser. No. 16/392,521, filed Apr. 23, 2019, which is a
continuation of U.S. application Ser. No. 14/590,483, filed Jan. 6,
2015, now U.S. Pat. No. 10,314,525, which is a continuation of U.S.
application Ser. No. 13/909,962, filed Jun. 4, 2013, now U.S. Pat.
No. 9,247,900, which is a continuation of U.S. application Ser. No.
11/360,262, filed Feb. 22, 2006, now U.S. Pat. No. 8,615,282. This
application is a continuation-in-part of U.S. application Ser. No.
16/133,469, filed Sep. 17, 2018, which is a continuation of U.S.
application Ser. No. 15/686,650, filed Aug. 25, 2017, now
abandoned, which is a continuation of U.S. application Ser. No.
14/144,523, filed Dec. 30, 2013, now U.S. Pat. No. 9,775,543, which
is a continuation of U.S. application Ser. No. 12/749,139, filed
Mar. 29, 2010, now U.S. Pat. No. 8,663,109 which is a continuation
of U.S. application Ser. No. 11/157,365, filed Jun. 21, 2005, now
U.S. Pat. No. 7,905,833. This application is a continuation-in-part
of U.S. application Ser. No. 16/179,662, filed Nov. 2, 2018, which
is a continuation of U.S. application Ser. No. 15/891,201, filed
Feb. 7, 2018, now abandoned, which is a continuation of U.S.
application Ser. No. 14/293,298, filed Jun. 2, 2014, now abandoned,
which is a continuation of U.S. application Ser. No. 13/361,820,
filed Jan. 30, 2012, now U.S. Pat. No. 8,968,198, which is a
continuation of U.S. application Ser. No. 11/360,250, filed Feb.
22, 2006, now U.S. Pat. No. 8,133,178. Each of the aforementioned
applications is incorporated by reference herein in its entirety,
and each is hereby expressly made a part of this specification.
Claims
What is claimed is:
1. A system for measuring an analyte concentration in a host, the
system comprising: a sensor system comprising: a first component
comprising a transcutaneous analyte sensor, wherein the
transcutaneous analyte sensor is configured to measure a signal
indicative of an analyte concentration in the host, wherein the
transcutaneous analyte sensor comprises: an in vivo portion
configured for insertion and existence within a living body of the
host during sensor use; and an ex vivo portion configured to remain
outside the living body of the host during sensor use; and a second
component comprising sensor electronics configured to operably
connect with the transcutaneous analyte sensor during sensor use,
wherein the sensor electronics comprise: one or more memories
configured to store: data representative of analyte concentrations
derived from signal measurements from the transcutaneous analyte
sensor; and sensor calibration information for calibration of the
transcutaneous analyte sensor without requiring a reference analyte
value; wherein the first component is unconnected to the second
component in a first state, wherein during a second state the first
component is configured to be connected to the second component by
the host to form an assembly prior to the assembly being affixed to
the host for sensor insertion.
2. The system for measuring an analyte concentration in a host of
claim 1, wherein the system is configured to have a sensor lifetime
of about 14 days.
3. The system for measuring an analyte concentration in a host of
claim 1, wherein the sensor electronics is configured to work in
concert with the transcutaneous analyte sensor to generate analyte
concentration measurements.
4. The system for measuring an analyte concentration in a host of
claim 1, wherein the sensor electronics are disposed inside a
housing having a height of from 0.075 inches to 0.2 inches.
5. The system for measuring an analyte concentration in a host of
claim 1, wherein the sensor electronics further comprise: a radio
frequency module.
6. The system for measuring an analyte concentration in a host of
claim 5, wherein the sensor electronics further comprise: a
temperature sensor configured to generate temperature data for
temperature compensation of a value associated with analyte
concentration; and an internal power source, wherein the internal
power source comprises a disposable battery having a height from
0.08 to 0.125 inches.
7. The system of claim 6, wherein the disposable battery supplies
power for a bias voltage applied to the transcutaneous analyte
sensor by the sensor electronics.
8. The system for measuring an analyte concentration in a host of
claim 5, the sensor system further comprising: a receiver
comprising: a processor configured to cause interrogation of the
radio frequency module, and to process data received from the radio
frequency module by the interrogation, wherein the interrogation
comprises use of inductive coupling; and a display configured to
display an estimated analyte concentration value associated with
the processed data.
9. The system of claim 8, wherein the radio frequency module is
configured to transmit information representative of the analyte
concentration to the receiver in response to the receiver
interrogating the sensor electronics.
10. The system of claim 9, wherein the receiver is configured to
provide inductive power to the sensor electronics during the
interrogation.
11. The system of claim 8, wherein the receiver is configured to
supply inductive power for data retrieval from the sensor
electronics.
Description
FIELD OF THE INVENTION
The present invention relates generally to systems and methods for
measuring an analyte in a host. More particularly, the present
invention relates to systems and methods for transcutaneous
measurement of glucose in a host.
BACKGROUND OF THE INVENTION
Diabetes mellitus is a disorder in which the pancreas cannot create
sufficient insulin (Type I or insulin dependent) and/or in which
insulin is not effective (Type 2 or non-insulin dependent). In the
diabetic state, the victim suffers from high blood sugar, which can
cause an array of physiological derangements associated with the
deterioration of small blood vessels, for example, kidney failure,
skin ulcers, or bleeding into the vitreous of the eye. A
hypoglycemic reaction (low blood sugar) can be induced by an
inadvertent overdose of insulin, or after a normal dose of insulin
or glucose-lowering agent accompanied by extraordinary exercise or
insufficient food intake.
Conventionally, a person with diabetes carries a self-monitoring
blood glucose (SMBG) monitor, which typically requires
uncomfortable finger pricking methods. Due to the lack of comfort
and convenience, a person with diabetes normally only measures his
or her glucose levels two to four times per day. Unfortunately,
such time intervals are so far spread apart that the person with
diabetes likely finds out too late of a hyperglycemic or
hypoglycemic condition, sometimes incurring dangerous side effects.
It is not only unlikely that a person with diabetes will take a
timely SMBG value, it is also likely that he or she will not know
if his or her blood glucose value is going up (higher) or down
(lower) based on conventional method. This inhibits the ability to
make educated insulin therapy decisions.
SUMMARY OF THE INVENTION
In a first aspect, a sensor system for measuring an analyte
concentration in a host is provided, the system comprising a sensor
configured to continuously measure an analyte concentration in a
host; a housing configured to receive the sensor, wherein the
housing is adapted for placement adjacent to the host's skin; an
electronics unit releasably attached to the housing, wherein the
electronics unit is operatively connected to the sensor and
comprises a processor module configured to provide a signal
associated with the analyte concentration in the host, and wherein
the processor module is further configured to assemble a data
packet for transmission; and an antenna configured for radiating or
receiving a radio frequency transmission, wherein the antenna is
located remote from the electronics unit.
In an embodiment of the first aspect, the system further comprises
an adhesive layer disposed on the housing and configured to adhere
the housing to the host's skin, wherein the antenna is located in
the adhesive layer or on the adhesive layer.
In an embodiment of the first aspect, the adhesive layer is
configured for use with only one sensor and the electronics unit is
configured for reuse with more than one sensor.
In an embodiment of the first aspect, the antenna is located in the
housing or on the housing.
In an embodiment of the first aspect, the housing is configured for
use with only one sensor and the electronics unit is configured for
reuse with more than one sensor.
In an embodiment of the first aspect, the antenna extends
substantially around a periphery of the housing.
In an embodiment of the first aspect, the system further comprises
a power source configured and arranged to power at least one of the
sensor and the electronics unit.
In an embodiment of the first aspect, the system further comprises
an adhesive layer disposed on the housing and configured to adhere
the housing to the host's skin, wherein the power source is located
in the adhesive or on the adhesive.
In an embodiment of the first aspect, the adhesive layer is
configured for use with only one sensor and the electronics unit is
configured for reuse with more than one sensor.
In an embodiment of the first aspect, the power source comprises a
thin and flexible battery.
In an embodiment of the first aspect, the power source is located
in the housing or on the housing.
In an embodiment of the first aspect, the housing is configured for
use with only one sensor and the electronics unit is configured for
reuse with more than one sensor.
In an embodiment of the first aspect, a height of the electronics
unit is no more than about 0.250 inches in its smallest
dimension.
In an embodiment of the first aspect, an overall height of the
system is no more than about 0.250 inches in its smallest
dimension.
In an embodiment of the first aspect, the sensor is configured for
insertion into the host's tissue.
In a second aspect, a sensor system for measuring an analyte
concentration in a host is provided, the system comprising a sensor
configured for insertion into a host's tissue, wherein the sensor
is configured to continuously measure an analyte concentration in a
host; a housing configured to receive the sensor, wherein the
housing is adapted for placement adjacent to the host's skin; and
an electronics unit releasably attached to the housing, wherein the
electronics unit is operatively connected to the sensor and
comprises a processor module configured to provide a signal
associated with the analyte concentration in the host.
In an embodiment of the second aspect, the housing comprises a
flexible material, and wherein the electronics unit and housing are
configured and arranged such that the electronics unit is released
from the housing by a flexing of the housing.
In an embodiment of the second aspect, the housing is configured
for use with only one sensor and the electronics unit is configured
for reuse with more than one sensor, and wherein the housing and
electronics unit are configured such that the housing physically
breaks upon release of the electronics unit.
In an embodiment of the second aspect, the system further comprises
a tool configured and arranged to assist a user in releasing the
electronics unit from the housing.
In an embodiment of the second aspect, the system further comprises
an antenna configured for radiating or receiving a radio frequency
transmission, wherein the antenna is located remote from the
electronics unit.
In a third aspect, a sensor system for measuring an analyte
concentration in a host is provided, the system comprising a sensor
configured to continuously measure an analyte concentration in a
host; a housing configured to receive the sensor, wherein the
housing is adapted for placement adjacent to the host's skin; an
electronics module associated with the housing, wherein the
electronics module is configured to provide a signal associated
with the analyte concentration in the host; and a power source
configured to power at least one of the sensor and the electronics
module.
In an embodiment of the third aspect, the system further comprises
an adhesive layer disposed on the housing and configured to adhere
the housing to the host's skin, wherein the power source located in
the adhesive layer or on the adhesive layer.
In an embodiment of the third aspect, the power source located in
the housing or on the housing.
In an embodiment of the third aspect, the power source comprises a
thin battery.
In an embodiment of the third aspect, the battery has a height of
no more than about 0.125 inches in its smallest dimension.
In an embodiment of the third aspect, the battery is flexible.
In an embodiment of the third aspect, the electronics module is
housed within an electronics unit, wherein the electronics unit is
attachable to and detachable from the housing, and wherein the
power source is configured to turn on when the electronics unit is
attached to the housing.
In an embodiment of the third aspect, the system further comprises
a switch selected from the group consisting of a bi-stable magnetic
reed switch, a proximity switch, and a motion-activated switch,
wherein the switch is configured to turn the power source on when
the electronics unit is attached to the housing.
In an embodiment of the third aspect, the power source is
configured to turn off when the electronics unit is detached from
the housing.
In an embodiment of the third aspect, the power source is a
motion-driven power source.
In an embodiment of the third aspect, the power source is a glucose
consumption-driven power source.
In an embodiment of the third aspect, an overall height of the
system is no more than about 0.350 inches in its smallest
dimension.
In an embodiment of the third aspect, the sensor is configured for
insertion into the host's tissue.
In a fourth aspect, a sensor for measurement of an analyte
concentration in a host is provided, the sensor comprising a first
wire electrode and a second wire electrode; a membrane system
disposed on an electroactive portion of the first wire electrode,
wherein the second wire electrode is coiled around the first wire
electrode at least up to an edge of the electroactive portion of
the first wire electrode.
In an embodiment of the fourth aspect, the second wire electrode is
coiled around the first wire electrode over at least a portion of
the electroactive portion of the first wire electrode
In an embodiment of the fourth aspect, the first wire electrode is
a working electrode and wherein the second wire electrode is at
least one of a reference electrode and a counter electrode.
In a fifth aspect, a sensor system for measuring an analyte
concentration in a host is provided, the system comprising a sensor
configured to continuously measure an analyte concentration in a
host; a laminate housing configured to receive the sensor, wherein
the laminate housing is adapted for placement adjacent to the
host's skin, and wherein the laminate housing comprises electronics
operatively connected to the sensor and comprising a processor
module configured to provide a signal associated with the analyte
concentration in the host; a power source configured to power at
least one of the sensor and the electronics; an antenna configured
for radiating or receiving a radio frequency transmission; and an
adhesive layer configured to adhere the housing to the host's
skin.
In an embodiment of the fifth aspect, the system is configured for
single-use.
In an embodiment of the fifth aspect, an overall height of the
laminate housing is no more than about 0.250 inches in its smallest
dimension.
In an embodiment of the fifth aspect, an aspect ratio of the
laminate housing is at least about 10:1.
In an embodiment of the fifth aspect, the sensor comprises a first
electrode and a second electrode, wherein the first electrode
comprises a working electrode, wherein the second electrode
comprises at least one of a reference electrode and a counter
electrode, and wherein the second electrode is located on the
adhesive layer.
In an embodiment of the fifth aspect, the electronics comprise a
flexible circuit board.
In an embodiment of the fifth aspect, the flexible circuit board is
at least one of disposed in the adhesive layer, disposed on the
adhesive layer, and laminated to the adhesive layer.
In an embodiment of the fifth aspect, the flexible circuit board is
no more than about 0.200 inches in its smallest dimension.
In an embodiment of the fifth aspect, the power source comprises a
flexible battery.
In an embodiment of the fifth aspect, the flexible battery is at
least one of disposed in the adhesive layer and laminated to the
adhesive layer.
In an embodiment of the fifth aspect, the flexible battery is no
more than about 0.200 inches in its smallest dimension.
In an embodiment of the fifth aspect, the antenna is at least one
of disposed in the adhesive layer, disposed on the adhesive layer,
and laminated to the adhesive layer.
In an embodiment of the fifth aspect, the laminate housing is water
resistant.
In an embodiment of the fifth aspect, the laminate housing is
waterproof.
In an embodiment of the fifth aspect, the laminate housing is
hermetically sealed.
In an embodiment of the fifth aspect, the electronics further
comprise a conductive material that only conducts in the
z-axis.
In an embodiment of the fifth aspect, the system further comprises
a cannula layer configured to receive the sensor, wherein the
cannula layer is configured to be released from the system after
sensor insertion.
In an embodiment of the fifth aspect, the sensor is configured for
insertion into the host's tissue.
In a sixth aspect, a sensor system for measuring an analyte
concentration in a host is provided, the system comprising a sensor
configured for insertion into the host's tissue, wherein the sensor
is configured to continuously measure an analyte concentration in a
host; a thin and flexible housing formed from a plurality of layers
and configured to receive the sensor, wherein the thin and flexible
housing is adapted for placement adjacent to the host's skin,
wherein the thin and flexible housing comprises electronics
operatively connected to the sensor and comprising a processor
module configured to provide a signal associated with the analyte
concentration in the host, wherein the electronics are located on a
thin and flexible substrate; a power source configured to power at
least one of the sensor and the electronics, wherein the power
source is located on the thin and flexible substrate; an antenna
configured for radiating or receiving a radio frequency
transmission, wherein the antenna is located on the thin and
flexible substrate; and an adhesive layer configured to adhere the
housing to the host's skin.
In an embodiment of the sixth aspect, the system is configured for
single-use.
In an embodiment of the sixth aspect, an overall height of the
laminate housing is no more than about 0.250 in its smallest
dimension.
In an embodiment of the sixth aspect, an aspect ratio of the
laminate housing is at least about 10:1.
In an embodiment of the sixth aspect, the laminate housing is water
resistant.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a transcutaneous analyte sensor
system, including an applicator, a mounting unit, and an
electronics unit.
FIG. 2 is a perspective view of a mounting unit, including the
electronics unit in its functional position.
FIG. 3 is an exploded perspective view of a mounting unit, showing
its individual components.
FIG. 4A is an exploded perspective view of a contact subassembly,
showing its individual components.
FIG. 4B is a perspective view of an alternative contact
configuration.
FIG. 4C is a perspective view of another alternative contact
configuration.
FIG. 5A is an expanded cutaway view of a proximal portion of a
sensor.
FIG. 5B is an expanded cutaway view of a distal portion of a
sensor.
FIG. 5C is a cross-sectional view through the sensor of FIG. 5B on
line C-C, showing an exposed electroactive surface of a working
electrode surrounded by a membrane system.
FIG. 6 is an exploded side view of an applicator, showing the
components that facilitate sensor insertion and subsequent needle
retraction.
FIGS. 7A to 7D are schematic side cross-sectional views that
illustrate applicator components and their cooperating
relationships.
FIG. 8A is a perspective view of an applicator and mounting unit in
one embodiment including a safety latch mechanism.
FIG. 8B is a side view of an applicator matingly engaged to a
mounting unit in one embodiment, prior to sensor insertion.
FIG. 8C is a side view of a mounting unit and applicator depicted
in the embodiment of FIG. 8B, after the plunger subassembly has
been pushed, extending the needle and sensor from the mounting
unit.
FIG. 8D is a side view of a mounting unit and applicator depicted
in the embodiment of FIG. 8B, after the guide tube subassembly has
been retracted, retracting the needle back into the applicator.
FIG. 8E is a perspective view of an applicator, in an alternative
embodiment, matingly engaged to the mounting unit after to sensor
insertion.
FIG. 8F is a perspective view of the mounting unit and applicator,
as depicted in the alternative embodiment of FIG. 8E, matingly
engaged while the electronics unit is slidingly inserted into the
mounting unit.
FIG. 8G is a perspective view of the electronics unit, as depicted
in the alternative embodiment of FIG. 8E, matingly engaged to the
mounting unit after the applicator has been released.
FIGS. 8H and 8I are comparative top views of the sensor system
shown in the alternative embodiment illustrated in FIGS. 8E to 8G
as compared to the embodiments illustrated in FIGS. 8B to 8D.
FIG. 8J is a perspective view of a sensor system showing the
electronics unit releasably attached to the housing and the safety
latch mechanism in one embodiment. FIG. 8K is a perspective view of
the sensor system of FIG. 8J showing the electronics unit
releasably attached to the housing and the safety latch mechanism
engaging the electronics unit/housing subassembly.
FIGS. 9A to 9C are side views of an applicator and mounting unit,
showing stages of sensor insertion.
FIGS. 10A and 10B are perspective and side cross-sectional views,
respectively, of a sensor system showing the mounting unit
immediately following sensor insertion and release of the
applicator from the mounting unit.
FIGS. 11A and 11B are perspective and side cross-sectional views,
respectively, of a sensor system showing the mounting unit after
pivoting the contact subassembly to its functional position.
FIGS. 12A to 12C are perspective and side views, respectively, of
the sensor system showing the sensor, mounting unit, and
electronics unit in their functional positions.
FIG. 13 is a block diagram that illustrates electronics associated
with a sensor system.
FIG. 14 is a perspective view of a sensor system wirelessly
communicating with a receiver.
FIG. 15A is a block diagram that illustrates a configuration of a
medical device including a continuous analyte sensor, a receiver,
and an external device.
FIGS. 15B to 15D are illustrations of receiver liquid crystal
displays showing embodiments of screen displays.
FIG. 16A is a flow chart that illustrates the initial calibration
and data output of sensor data.
FIG. 16B is a graph that illustrates one example of using prior
information for slope and baseline.
FIG. 17 is a flow chart that illustrates evaluation of reference
and/or sensor data for statistical, clinical, and/or physiological
acceptability.
FIG. 18 is a flow chart that illustrates evaluation of calibrated
sensor data for aberrant values.
FIG. 19 is a flow chart that illustrates self-diagnostics of sensor
data.
FIGS. 20A and 20B are graphical representations of glucose sensor
data in a human obtained over approximately three days.
FIG. 21 is a graphical representation of glucose sensor data in a
human obtained over approximately seven days.
FIG. 22A is a perspective view of a sensor system including a
disposable thin laminate sensor housing in one embodiment.
FIGS. 22B and 22C are cut-away side cross-sectional views of the
thin, laminate, flexible sensor system in one embodiment.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The following description and examples illustrate some exemplary
embodiments of the disclosed invention in detail. Those of skill in
the art will recognize that there are numerous variations and
modifications of this invention that are encompassed by its scope.
Accordingly, the description of a certain exemplary embodiment
should not be deemed to limit the scope of the present
invention.
Definitions
In order to facilitate an understanding of the preferred
embodiments, a number of terms are defined below.
The term "analyte" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and is not to be limited to a special or
customized meaning), and refers without limitation to a substance
or chemical constituent in a biological fluid (for example, blood,
interstitial fluid, cerebral spinal fluid, lymph fluid or urine)
that can be analyzed. Analytes can include naturally occurring
substances, artificial substances, metabolites, and/or reaction
products. In some embodiments, the analyte for measurement by the
sensing regions, devices, and methods is glucose. However, other
analytes are contemplated as well, including but not limited to
acarboxyprothrombin; acylcarnitine; adenine phosphoribosyl
transferase; adenosine deaminase; albumin; alpha-fetoprotein; amino
acid profiles (arginine (Krebs cycle), histidine/urocanic acid,
homocysteine, phenylalanine/tyrosine, tryptophan);
andrenostenedione; antipyrine; arabinitol enantiomers; arginase;
benzoylecgonine (cocaine); biotinidase; biopterin; c-reactive
protein; carnitine; carnosinase; CD4; ceruloplasmin;
chenodeoxycholic acid; chloroquine; cholesterol; cholinesterase;
conjugated 1- hydroxy-cholic acid; cortisol; creatine kinase;
creatine kinase MM isoenzyme; cyclosporin A; d-penicillamine;
de-ethylchloroquine; dehydroepiandrosterone sulfate; DNA
(acetylator polymorphism, alcohol dehydrogenase, alpha
1-antitrypsin, cystic fibrosis, Duchenne/Becker muscular dystrophy,
glucose-6-phosphate dehydrogenase, hemoglobin A, hemoglobin S,
hemoglobin C, hemoglobin D, hemoglobin E, hemoglobin F, D-Punjab,
beta-thalassemia, hepatitis B virus, HCMV, HTLV-1, Leber hereditary
optic neuropathy, MCAD, RNA, PKU, Plasmodium vivax, sexual
differentiation, 21-deoxycortisol); desbutylhalofantrine;
dihydropteridine reductase; diptheria/tetanus antitoxin;
erythrocyte arginase; erythrocyte protoporphyrin; esterase D; fatty
acids/acylglycines; free -human chorionic gonadotropin; free
erythrocyte porphyrin; free thyroxine (FT4); free tri-iodothyronine
(FT3); fumarylacetoacetase; galactose/gal-1-phosphate;
galactose-1-phosphate uridyltransferase; gentamicin;
glucose-6-phosphate dehydrogenase; glutathione; glutathione
perioxidase; glycocholic acid; glycosylated hemoglobin;
halofantrine; hemoglobin variants; hexosaminidase A; human
erythrocyte carbonic anhydrase I; 17-alpha-hydroxyprogesterone;
hypoxanthine phosphoribosyl transferase; immunoreactive trypsin;
lactate; lead; lipoproteins ((a), B/A-1, ); lysozyme; mefloquine;
netilmicin; phenobarbitone; phenytoin; phytanic/pristanic acid;
progesterone; prolactin; prolidase; purine nucleoside
phosphorylase; quinine; reverse tri-iodothyronine (rT3); selenium;
serum pancreatic lipase; sissomicin; somatomedin C; specific
antibodies (adenovirus, anti-nuclear antibody, anti-zeta antibody,
arbovirus, Aujeszky's disease virus, dengue virus, Dracunculus
medinensis, Echinococcus granulosus, Entamoeba histolytica,
enterovirus, Giardia duodenalisa, Helicobacter pylori, hepatitis B
virus, herpes virus, HIV-1, IgE (atopic disease), influenza virus,
Leishmania donovani, leptospira, measles/mumps/rubella,
Mycobacterium leprae, Mycoplasma pneumoniae, Myoglobin, Onchocerca
volvulus, parainfluenza virus, Plasmodium falciparum, poliovirus,
Pseudomonas aeruginosa, respiratory syncytial virus, rickettsia
(scrub typhus), Schistosoma mansoni, Toxoplasma gondii, Trepenoma
pallidium, Trypanosoma cruzi/rangeli, vesicular stomatis virus,
Wuchereria bancrofti, yellow fever virus); specific antigens
(hepatitis B virus, HIV-1); succinylacetone; sulfadoxine;
theophylline; thyrotropin (TSH); thyroxine (T4); thyroxine-binding
globulin; trace elements; transferrin; UDP-galactose-4-epimerase;
urea; uroporphyrinogen I synthase; vitamin A; white blood cells;
and zinc protoporphyrin. Salts, sugar, protein, fat, vitamins, and
hormones naturally occurring in blood or interstitial fluids can
also constitute analytes in certain embodiments. The analyte can be
naturally present in the biological fluid, for example, a metabolic
product, a hormone, an antigen, an antibody, and the like.
Alternatively, the analyte can be introduced into the body, for
example, a contrast agent for imaging, a radioisotope, a chemical
agent, a fluorocarbon-based synthetic blood, or a drug or
pharmaceutical composition, including but not limited to insulin;
ethanol; cannabis (marijuana, tetrahydrocannabinol, hashish);
inhalants (nitrous oxide, amyl nitrite, butyl nitrite,
chlorohydrocarbons, hydrocarbons); cocaine (crack cocaine);
stimulants (amphetamines, methamphetamines, Ritalin, Cylert,
Preludin, Didrex, PreState, Voranil, Sandrex, Plegine); depressants
(barbituates, methaqualone, tranquilizers such as Valium, Librium,
Miltown, Serax, Equanil, Tranxene); hallucinogens (phencyclidine,
lysergic acid, mescaline, peyote, psilocybin); narcotics (heroin,
codeine, morphine, opium, meperidine, Percocet, Percodan,
Tussionex, Fentanyl, Darvon, Talwin, Lomotil); designer drugs
(analogs of fentanyl, meperidine, amphetamines, methamphetamines,
and phencyclidine, for example, Ecstasy); anabolic steroids; and
nicotine. The metabolic products of drugs and pharmaceutical
compositions are also contemplated analytes. Analytes such as
neurochemicals and other chemicals generated within the body can
also be analyzed, such as, for example, ascorbic acid, uric acid,
dopamine, noradrenaline, 3-methoxytyramine (3MT),
3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA),
5-hydroxytryptamine (5HT), and 5-hydroxyindoleacetic acid
(FHIAA).
The term "host" as used herein is a broad term, and is to be given
its ordinary and customary meaning to a person of ordinary skill in
the art (and is not to be limited to a special or customized
meaning), and refers without limitation to mammals, particularly
humans.
The term "exit-site" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and is not to be limited to a special or
customized meaning), and refers without limitation to the area
where a medical device (for example, a sensor and/or needle) exits
from the host's body.
The phrase "continuous (or continual) analyte sensing" as used
herein is a broad term, and is to be given its ordinary and
customary meaning to a person of ordinary skill in the art (and is
not to be limited to a special or customized meaning), and refers
without limitation to the period in which monitoring of analyte
concentration is continuously, continually, and or intermittently
(regularly or irregularly) performed, for example, about every 5 to
10 minutes.
The term "electrochemically reactive surface" as used herein is a
broad term, and is to be given its ordinary and customary meaning
to a person of ordinary skill in the art (and is not to be limited
to a special or customized meaning), and refers without limitation
to the surface of an electrode where an electrochemical reaction
takes place. For example, a working electrode measures hydrogen
peroxide produced by the enzyme-catalyzed reaction of the analyte
detected, which reacts to create an electric current. Glucose
analyte can be detected utilizing glucose oxidase, which produces
H.sub.2O.sub.2 as a byproduct. H.sub.2O.sub.2 reacts with the
surface of the working electrode, producing two protons (2H.sup.+),
two electrons (2e.sup.-) and one molecule of oxygen (O.sub.2),
which produces the electronic current being detected.
The term "electronic connection" as used herein is a broad term,
and is to be given its ordinary and customary meaning to a person
of ordinary skill in the art (and is not to be limited to a special
or customized meaning), and refers without limitation to any
electronic connection known to those in the art that can be
utilized to interface the sensing region electrodes with the
electronic circuitry of a device, such as mechanical (for example,
pin and socket) or soldered electronic connections.
The terms "interferant" and "interferants" as used herein are broad
terms, and are to be given their ordinary and customary meaning to
a person of ordinary skill in the art (and are not to be limited to
a special or customized meaning), and refer without limitation to
species that interfere with the measurement of an analyte of
interest in a sensor to produce a signal that does not accurately
represent the analyte measurement. In one example of an
electrochemical sensor, interferants are compounds with oxidation
potentials that overlap with the analyte to be measured.
The term "sensing region" as used herein is a broad term, and is to
be given its ordinary and customary meaning to a person of ordinary
skill in the art (and is not to be limited to a special or
customized meaning), and refers without limitation to the region of
a monitoring device responsible for the detection of a particular
analyte. The sensing region generally comprises a non-conductive
body, a working electrode (anode), a reference electrode
(optional), and/or a counter electrode (cathode) passing through
and secured within the body forming electrochemically reactive
surfaces on the body and an electronic connective means at another
location on the body, and a multi-domain membrane affixed to the
body and covering the electrochemically reactive surface.
The term "high oxygen solubility domain" as used herein is a broad
term, and is to be given its ordinary and customary meaning to a
person of ordinary skill in the art (and is not to be limited to a
special or customized meaning), and refers without limitation to a
domain composed of a material that has higher oxygen solubility
than aqueous media such that it concentrates oxygen from the
biological fluid surrounding the membrane system. The domain can
act as an oxygen reservoir during times of minimal oxygen need and
has the capacity to provide, on demand, a higher oxygen gradient to
facilitate oxygen transport across the membrane. Thus, the ability
of the high oxygen solubility domain to supply a higher flux of
oxygen to critical domains when needed can improve overall sensor
function.
The term "domain" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and is not to be limited to a special or
customized meaning), and refers without limitation to a region of
the membrane system that can be a layer, a uniform or non-uniform
gradient (for example, an anisotropic region of a membrane), or a
portion of a membrane.
The phrase "distal to" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and is not to be limited to a special or
customized meaning), and refers without limitation to the spatial
relationship between various elements in comparison to a particular
point of reference. In general, the term indicates an element is
located relatively far from the reference point than another
element.
The term "proximal to" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and is not to be limited to a special or
customized meaning), and refers without limitation to the spatial
relationship between various elements in comparison to a particular
point of reference. In general, the term indicates an element is
located relatively near to the reference point than another
element.
The terms "in vivo portion" and "distal portion" as used herein are
broad terms, and are to be given their ordinary and customary
meaning to a person of ordinary skill in the art (and are not to be
limited to a special or customized meaning), and refer without
limitation to the portion of the device (for example, a sensor)
adapted for insertion into and/or existence within a living body of
a host.
The terms "ex vivo portion" and "proximal portion" as used herein
are broad terms, and are to be given their ordinary and customary
meaning to a person of ordinary skill in the art (and are not to be
limited to a special or customized meaning), and refer without
limitation to the portion of the device (for example, a sensor)
adapted to remain and/or exist outside of a living body of a
host.
The terms "raw data stream," "signal" and "data stream" as used
herein are broad terms, and are to be given their ordinary and
customary meaning to a person of ordinary skill in the art (and are
not to be limited to a special or customized meaning), and refer
without limitation to an analog or digital signal from the analyte
sensor directly related to the measured analyte. For example, the
raw data stream is digital data in "counts" converted by an A/D
converter from an analog signal (for example, voltage or amps)
representative of an analyte concentration. The terms broadly
encompass a plurality of time spaced data points from a
substantially continuous analyte sensor, each of which comprises
individual measurements taken at time intervals ranging from
fractions of a second up to, for example, 1, 2, or 5 minutes or
longer.
The term "count" as used herein is a broad term, and is to be given
its ordinary and customary meaning to a person of ordinary skill in
the art (and is not to be limited to a special or customized
meaning), and refers without limitation to a unit of measurement of
a digital signal. For example, a raw data stream measured in counts
is directly related to a voltage (for example, converted by an A/D
converter), which is directly related to current from the working
electrode.
The term "physiologically feasible" as used herein is a broad term,
and is to be given its ordinary and customary meaning to a person
of ordinary skill in the art (and is not to be limited to a special
or customized meaning), and refers without limitation to one or
more physiological parameters obtained from continuous studies of
glucose data in humans and/or animals. For example, a maximal
sustained rate of change of glucose in humans of about 4 to 6
mg/dL/min and a maximum acceleration of the rate of change of about
0.1 to 0.2 mg/dL/min/min are deemed physiologically feasible
limits. Values outside of these limits are considered
non-physiological and are likely a result of, e.g., signal
error.
The term "ischemia" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and is not to be limited to a special or
customized meaning), and refers without limitation to local and
temporary deficiency of blood supply due to obstruction of
circulation to a part (for example, a sensor). Ischemia can be
caused, for example, by mechanical obstruction (for example,
arterial narrowing or disruption) of the blood supply.
The term "matched data pairs" as used herein is a broad term, and
is to be given its ordinary and customary meaning to a person of
ordinary skill in the art (and is not to be limited to a special or
customized meaning), and refers without limitation to reference
data (for example, one or more reference analyte data points)
matched with substantially time corresponding sensor data (for
example, one or more sensor data points).
The term "Clarke Error Grid" as used herein is a broad term, and is
to be given its ordinary and customary meaning to a person of
ordinary skill in the art (and is not to be limited to a special or
customized meaning), and refers without limitation to an error grid
analysis, for example, an error grid analysis used to evaluate the
clinical significance of the difference between a reference glucose
value and a sensor generated glucose value, taking into account 1)
the value of the reference glucose measurement, 2) the value of the
sensor glucose measurement, 3) the relative difference between the
two values, and 4) the clinical significance of this difference.
See Clarke et al., "Evaluating Clinical Accuracy of Systems for
Self-Monitoring of Blood Glucose", Diabetes Care, Volume 10, Number
5, September-October 1987, the contents of which are hereby
incorporated by reference herein in their entirety and are hereby
made a part of this specification.
The term "Consensus Error Grid" as used herein is a broad term, and
is to be given its ordinary and customary meaning to a person of
ordinary skill in the art (and is not to be limited to a special or
customized meaning), and refers without limitation to an error grid
analysis that assigns a specific level of clinical risk to any
possible error between two time corresponding measurements, e.g.,
glucose measurements. The Consensus Error Grid is divided into
zones signifying the degree of risk posed by the deviation. See
Parkes et al., "A New Consensus Error Grid to Evaluate the Clinical
Significance of Inaccuracies in the Measurement of Blood Glucose",
Diabetes Care, Volume 23, Number 8, August 2000, the contents of
which are hereby incorporated by reference herein in their entirety
and are hereby made a part of this specification.
The term "clinical acceptability" as used herein is a broad term,
and is to be given its ordinary and customary meaning to a person
of ordinary skill in the art (and is not to be limited to a special
or customized meaning), and refers without limitation to
determination of the risk of an inaccuracy to a patient. Clinical
acceptability considers a deviation between time corresponding
analyte measurements (for example, data from a glucose sensor and
data from a reference glucose monitor) and the risk (for example,
to the decision making of a person with diabetes) associated with
that deviation based on the analyte value indicated by the sensor
and/or reference data. An example of clinical acceptability can be
85% of a given set of measured analyte values within the "A" and
"B" region of a standard Clarke Error Grid when the sensor
measurements are compared to a standard reference measurement.
The term "sensor" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and is not to be limited to a special or
customized meaning), and refers without limitation to the component
or region of a device by which an analyte can be quantified.
The term "needle" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and is not to be limited to a special or
customized meaning), and refers without limitation to a slender
hollow instrument for introducing material into or removing
material from the body.
The terms "operably (or operatively) connected" and "operably (or
operatively) linked" as used herein are broad terms, and are to be
given their ordinary and customary meaning to a person of ordinary
skill in the art (and are not to be limited to a special or
customized meaning), and refer without limitation to one or more
components linked to one or more other components. The terms can
refer to a mechanical connection, an electrical connection, or a
connection that allows transmission of signals between the
components. For example, one or more electrodes can be used to
detect the amount of analyte in a sample and to convert that
information into a signal; the signal can then be transmitted to a
circuit. In such an example, the electrode is "operably linked" to
the electronic circuitry.
The term "baseline" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and is not to be limited to a special or
customized meaning), and refers without limitation to the component
of an analyte sensor signal that is not related to the analyte
concentration. In one example of a glucose sensor, the baseline is
composed substantially of signal contribution due to factors other
than glucose (for example, interfering species,
non-reaction-related hydrogen peroxide, or other electroactive
species with an oxidation potential that overlaps with hydrogen
peroxide). In some embodiments wherein a calibration is defined by
solving for the equation y=mx+b, the value of b represents the
baseline of the signal.
The terms "sensitivity" and "slope" as used herein are broad terms,
and are to be given their ordinary and customary meaning to a
person of ordinary skill in the art (and are not to be limited to a
special or customized meaning), and refer without limitation to an
amount of electrical current produced by a predetermined amount
(unit) of the measured analyte. For example, in one preferred
embodiment, a sensor has a sensitivity (or slope) of about 3.5 to
about 7.5 picoAmps of current for every 1 mg/dL of glucose
analyte.
The term "membrane system" as used herein is a broad term, and is
to be given its ordinary and customary meaning to a person of
ordinary skill in the art (and is not to be limited to a special or
customized meaning), and refers without limitation to a permeable
or semi-permeable membrane that can be comprised of two or more
domains and is typically constructed of materials of a few microns
thickness or more, which is permeable to oxygen and is optionally
permeable to, e.g., glucose or another analyte. In one example, the
membrane system comprises an immobilized glucose oxidase enzyme,
which enables a reaction to occur between glucose and oxygen
whereby a concentration of glucose can be measured.
The terms "processor module" and "microprocessor" as used herein
are broad terms, and are to be given their ordinary and customary
meaning to a person of ordinary skill in the art (and are not to be
limited to a special or customized meaning), and refer without
limitation to a computer system, state machine, processor, or the
like designed to perform arithmetic or logic operations using logic
circuitry that responds to and processes the basic instructions
that drive a computer.
The terms "smoothing" and "filtering" as used herein are broad
terms, and are to be given their ordinary and customary meaning to
a person of ordinary skill in the art (and are not to be limited to
a special or customized meaning), and refer without limitation to
modification of a set of data to make it smoother and more
continuous or to remove or diminish outlying points, for example,
by performing a moving average of the raw data stream.
The term "algorithm" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and is not to be limited to a special or
customized meaning), and refers without limitation to a
computational process (for example, programs) involved in
transforming information from one state to another, for example, by
using computer processing.
The term "regression" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and is not to be limited to a special or
customized meaning), and refers without limitation to finding a
line for which a set of data has a minimal measurement (for
example, deviation) from that line. Regression can be linear,
non-linear, first order, second order, or the like. One example of
regression is least squares regression.
The term "calibration" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and is not to be limited to a special or
customized meaning), and refers without limitation to the process
of determining the relationship between the sensor data and the
corresponding reference data, which can be used to convert sensor
data into meaningful values substantially equivalent to the
reference data. In some embodiments, namely, in continuous analyte
sensors, calibration can be updated or recalibrated over time as
changes in the relationship between the sensor data and reference
data occur, for example, due to changes in sensitivity, baseline,
transport, metabolism, or the like.
The terms "interferants" and "interfering species" as used herein
are broad terms, and are to be given their ordinary and customary
meaning to a person of ordinary skill in the art (and are not to be
limited to a special or customized meaning), and refer without
limitation to effects and/or species that interfere with the
measurement of an analyte of interest in a sensor to produce a
signal that does not accurately represent the analyte
concentration. In one example of an electrochemical sensor,
interfering species are compounds with an oxidation potential that
overlap that of the analyte to be measured, thereby producing a
false positive signal.
The terms "chloridization" and "chloridizing" as used herein are
broad terms, and are to be given their ordinary and customary
meaning to a person of ordinary skill in the art (and are not to be
limited to a special or customized meaning), and refer without
limitation to treatment or preparation with chloride. The term
"chloride" as used herein, is a broad term and is used in its
ordinary sense, including, without limitation, to refer to Cl.sup.-
ions, sources of Cl.sup.- ions, and salts of hydrochloric acid.
Chloridization and chloridizing methods include, but are not
limited to, chemical and electrochemical methods.
The terms "height," "depth" and "thickness" as used herein are
broad terms, and are to be given their ordinary and customary
meaning to a person of ordinary skill in the art (and are not to be
limited to a special or customized meaning), and refer without
limitation to the smallest of the three dimensions (x, y and z) of
an object.
The terms "substantially thin," "thin," "substantially flat,"
"flat," "substantially planar" and "planar" as used herein are
broad terms, and are to be given their ordinary and customary
meaning to a person of ordinary skill in the art (and are not to be
limited to a special or customized meaning), and refer without
limitation to having minimal size in a smallest dimension
(thickness) as compared to one or both of the larger two dimensions
of an object, for example, something that is not deep or thick. The
terms can be expressed as an aspect ratio, for example, when the
aspect ratio of the length and/or the width of an object as
compared its height is at least about 10:1, 15:1, 20:1, 30:1, 40:1,
or 50:1. In some embodiments, the terms can be expressed as an
aspect ratio, for example, when the aspect ratio of both the length
and the width of an object as compared its height is at least about
10:1, 15:1, 20:1, 30:1, 40:1, or 50:1.
The term "aspect ratio" as used herein is a broad term, and is to
be given its ordinary and customary meaning to a person of ordinary
skill in the art (and is not to be limited to a special or
customized meaning), and refers without limitation to a ratio of
the length or width of an object (not its smallest dimension) to
the height (its smallest dimension)
The terms "single-use" and "disposable" as used herein are broad
terms, and are to be given their ordinary and customary meaning to
a person of ordinary skill in the art (and are not to be limited to
a special or customized meaning), and refer without limitation to
something configured and arranged to be used only once, after which
it is intended to be disposed of.
The terms "reuse," "reusable" and "durable" as used herein are
broad terms, and are to be given their ordinary and customary
meaning to a person of ordinary skill in the art (and are not to be
limited to a special or customized meaning), and refer without
limitation to something configured and arranged to be used more
than once and not intended to be disposed of after only one
use.
The terms "laminate" and "laminated" as used herein are broad
terms, and are to be given their ordinary and customary meaning to
a person of ordinary skill in the art (and are not to be limited to
a special or customized meaning), and refer without limitation to a
structure formed from multiple layers and/or the process of its
formation. Preferably, the layers of a laminate structure are
substantially thin, flat, and/or planar.
The term "laminate housing" as used herein is a broad term, and is
to be given its ordinary and customary meaning to a person of
ordinary skill in the art (and is not to be limited to a special or
customized meaning), and refers without limitation to structure
including multiple layers with similar or different dimensions,
configurations, and/or arrangements and is broad enough to include
any superposition of one relatively thin structure (e.g., layer) of
any shape or size on top of another relative thin structure (e.g.,
layer) of any shape or size; namely, the "layers" need not be
similar in shape, size, configuration and/or function.
The term "water resistant" as used herein is a broad term, and is
to be given its ordinary and customary meaning to a person of
ordinary skill in the art (and is not to be limited to a special or
customized meaning), and refers without limitation to a property of
being resistant to penetration by water. The term can be defined by
any one of the ISO 2281 standards for water resistance of
watches.
The term "waterproof" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and is not to be limited to a special or
customized meaning), and refers without limitation to a property of
being impervious to or unaffected by water. The term can be defined
by any one of the IEC 60529:2001 or IPX standards for
waterproofness.
The terms "hermetic" and "hermetically sealed" as used herein are
broad terms, and are to be given their ordinary and customary
meaning to a person of ordinary skill in the art (and are not to be
limited to a special or customized meaning), and refer without
limitation to airtight.
Sensor System
A transcutaneous analyte sensor system is provided that includes an
applicator for inserting the transdermal analyte sensor under a
host's skin. The sensor system includes a sensor for sensing the
analyte, wherein the sensor is associated with a mounting unit
adapted for mounting on the skin of the host. The mounting unit
houses the electronics unit associated with the sensor and is
adapted for fastening to the host's skin. In certain embodiments,
the system further includes a receiver for receiving and/or
processing sensor data.
FIG. 1 is a perspective view of a transcutaneous analyte sensor
system 10. In the preferred embodiment of a system as depicted in
FIG. 1, the system includes an applicator 12, a mounting unit 14,
and an electronics unit 16. The system can further include a
receiver 158, such as is described in more detail with reference to
FIG. 14.
The mounting unit (also referred to as a housing) 14 includes a
base (also referred to as a housing) 24 adapted for mounting on the
skin of a host, a sensor adapted for transdermal insertion through
the skin of a host (see FIG. 4A), and one or more contacts 28
configured to provide secure electrical contact between the sensor
and the electronics unit 16. The mounting unit 14 is designed to
maintain the integrity of the sensor in the host so as to reduce or
eliminate translation of motion between the mounting unit, the
host, and/or the sensor.
In one embodiment, an applicator 12 is provided for inserting the
sensor 32 through the host's skin at the appropriate insertion
angle with the aid of a needle (see FIGS. 6 through 8), and for
subsequent removal of the needle using a continuous push-pull
action. Preferably, the applicator comprises an applicator body 18
that guides the applicator components (see FIGS. 6 through 8) and
includes an applicator body base 60 configured to mate with the
mounting unit 14 during insertion of the sensor into the host. The
mate between the applicator body base 60 and the mounting unit 14
can use any known mating configuration, for example, a snap-fit, a
press-fit, an interference-fit, or the like, to discourage
separation during use. One or more release latches 30 enable
release of the applicator body base 60, for example, when the
applicator body base 60 is snap fit into the mounting unit 14.
The electronics unit 16 includes hardware, firmware, and/or
software that enable measurement of levels of the analyte via the
sensor. For example, the electronics unit 16 can comprise a
potentiostat, a power source for providing power to the sensor,
other components useful for signal processing, and preferably an RF
(Radio Frequency) module for transmitting data from the electronics
unit 16 to a receiver (see FIGS. 13 to 15). Electronics can be
affixed to a printed circuit board (PCB), or the like, and can take
a variety of forms. For example, the electronics can take the form
of an integrated circuit (IC), such as an Application-Specific
Integrated Circuit (ASIC), a microcontroller, or a processor.
In some embodiments, the electronics unit includes a flexible
circuit board as a whole or part thereof, for example at least a
portion of the sensor electronics can be located on a flexible
circuit board. In some embodiments, single, double, multilayer, and
rigid flex capabilities can be provided by the flexible circuit
board. In some embodiments, the flexible circuit board can include
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more layers. In
some embodiments, the flexible circuit board is designed with a
thickness of from about 0.005, 0.010, 0.015, 0.020, 0.025, 0.030,
0.040, 0.050 inches or less to about 0.075, 0.080, 0.090, 0.100,
0.125 inches or more; while the length and width of the flexible
circuit board can be dictated as no larger than the overall length
and width of the sensor system or one of its components or
subassemblies. In some embodiments, the flexible circuit board is
at least one of disposed in the adhesive layer, disposed on the
adhesive layer, and laminated to the adhesive layer.
Preferably, electronics unit 16 houses the sensor electronics,
which comprise systems and methods for processing sensor analyte
data. Examples of systems and methods for processing sensor analyte
data are described in more detail below and in U.S. Patent
Publication No. US-2005-0027463-A1
After insertion of the sensor using the applicator 12, and
subsequent release of the applicator 12 from the mounting unit 14
(see FIGS. 8B to 8D), the electronics unit 16 is configured to
releasably mate with the mounting unit 14 in a manner similar to
that described above with reference to the applicator body base 60.
The electronics unit 16 includes contacts on its backside (not
shown) configured to electrically connect with the contacts 28,
such as are described in more detail with reference to FIGS. 2
through 4. In one embodiment, the electronics unit 16 is configured
with programming, for example initialization, calibration reset,
failure testing, or the like, each time it is initially inserted
into the mounting unit 14 and/or each time it initially
communicates with the sensor 32.
Mounting Unit
FIG. 2 is a perspective view of a sensor system of a preferred
embodiment, shown in its functional position, including a mounting
unit and an electronics unit matingly engaged therein. FIGS. 8 to
10 illustrate the sensor is its functional position for measurement
of an analyte concentration in a host.
In preferred embodiments, the mounting unit 14, also referred to as
a housing or a disposable housing, comprises a base 24 adapted for
fastening to a host's skin. The base can be formed from a variety
of hard or soft materials, and preferably comprises a low profile
for minimizing protrusion of the device from the host during use.
In some embodiments, the base 24 is formed at least partially from
a flexible material, which is believed to provide numerous
advantages over conventional transcutaneous sensors, which,
unfortunately, can suffer from motion-related artifacts associated
with the host's movement when the host is using the device. For
example, when a transcutaneous analyte sensor is inserted into the
host, various movements of the sensor (for example, relative
movement between the in vivo portion and the ex vivo portion,
movement of the skin, and/or movement within the host (dermis or
subcutaneous)) create stresses on the device and can produce noise
in the sensor signal. It is believed that even small movements of
the skin can translate to discomfort and/or motion-related
artifact, which can be reduced or obviated by a flexible or
articulated base. Thus, by providing flexibility and/or
articulation of the device against the host's skin, better
conformity of the sensor system 10 to the regular use and movements
of the host can be achieved. Flexibility or articulation is
believed to increase adhesion (with the use of an adhesive layer)
of the mounting unit 14 onto the skin, thereby decreasing
motion-related artifact that can otherwise translate from the
host's movements and reduced sensor performance.
FIG. 3 is an exploded perspective view of a sensor system of a
preferred embodiment, showing a mounting unit, an associated
contact subassembly, and an electronics unit. In some embodiments,
the contacts 28 are mounted on or in a subassembly hereinafter
referred to as a contact subassembly 26 (see FIG. 4A), which
includes a contact holder 34 configured to fit within the base 24
of the mounting unit 14 and a hinge 38 that allows the contact
subassembly 26 to pivot between a first position (for insertion)
and a second position (for use) relative to the mounting unit 14,
which is described in more detail with reference to FIGS. 10 and
11. The term "hinge" as used herein is a broad term and is used in
its ordinary sense, including, without limitation, to refer to any
of a variety of pivoting, articulating, and/or hinging mechanisms,
such as an adhesive hinge, a sliding joint, and the like; the term
hinge does not necessarily imply a fulcrum or fixed point about
which the articulation occurs.
In certain embodiments, the mounting unit 14 is provided with an
adhesive material or adhesive layer 8, also referred to as an
adhesive pad, preferably disposed on the mounting unit's back
surface and preferably including a releasable backing layer 9.
Thus, removing the backing layer 9 and pressing the base portion 24
of the mounting unit onto the host's skin adheres the mounting unit
14 to the host's skin. Additionally or alternatively, an adhesive
layer can be placed over some or all of the sensor system after
sensor insertion is complete to ensure adhesion, and optionally to
ensure an airtight seal or watertight seal around the wound
exit-site (or sensor insertion site) (not shown). Appropriate
adhesive layers can be chosen and designed to stretch, elongate,
conform to, and/or aerate the region (e.g., host's skin).
In preferred embodiments, the adhesive layer 8 is formed from
spun-laced, open- or closed-cell foam, and/or non-woven fibers, and
includes an adhesive disposed thereon, however a variety of
adhesive layers appropriate for adhesion to the host's skin can be
used, as is appreciated by one skilled in the art of medical
adhesive layers. In some embodiments, a double-sided adhesive layer
is used to adhere the mounting unit to the host's skin. In other
embodiments, the adhesive layer includes a foam layer, for example,
a layer wherein the foam is disposed between the adhesive layer's
side edges and acts as a shock absorber.
In some embodiments, the surface area of the adhesive layer 8 is
greater than the surface area of the mounting unit's back surface.
Alternatively, the adhesive layer can be sized with substantially
the same surface area as the back surface of the base portion.
Preferably, the adhesive layer has a surface area on the side to be
mounted on the host's skin that is greater than about 1, 1.25, 1.5,
1.75, 2, 2.25, or 2.5, times the surface area of the back surface
25 of the mounting unit base 24. Such a greater surface area can
increase adhesion between the mounting unit and the host's skin,
minimize movement between the mounting unit and the host's skin,
and/or protect the wound exit-site (sensor insertion site) from
environmental and/or biological contamination. In some alternative
embodiments, however, the adhesive layer can be smaller in surface
area than the back surface assuming a sufficient adhesion can be
accomplished.
In some embodiments, the adhesive layer 8 is substantially the same
shape as the back surface 25 of the base 24, although other shapes
can also be advantageously employed, for example, butterfly-shaped,
round, square, or rectangular. The adhesive layer backing can be
designed for two-step release, for example, a primary release
wherein only a portion of the adhesive layer is initially exposed
to allow adjustable positioning of the device, and a secondary
release wherein the remaining adhesive layer is later exposed to
firmly and securely adhere the device to the host's skin once
appropriately positioned. The adhesive layer is preferably
waterproof. Preferably, a stretch-release adhesive layer is
provided on the back surface of the base portion to enable easy
release from the host's skin at the end of the useable life of the
sensor, as is described in more detail with reference to FIGS. 9A
to 9C.
In some circumstances, it has been found that a conventional bond
between the adhesive layer and the mounting unit may not be
sufficient, for example, due to humidity that can cause release of
the adhesive layer from the mounting unit. Accordingly, in some
embodiments, the adhesive layer can be bonded using a bonding agent
activated by or accelerated by an ultraviolet, acoustic, radio
frequency, or humidity cure. In some embodiments, a eutectic bond
of first and second composite materials can form a strong adhesion.
In some embodiments, the surface of the mounting unit can be
pretreated utilizing ozone, plasma, chemicals, or the like, in
order to enhance the bondability of the surface.
A bioactive agent is preferably applied locally at the insertion
site (exit-site) prior to or during sensor insertion. Suitable
bioactive agents include those which are known to discourage or
prevent bacterial growth and infection, for example,
anti-inflammatory agents, antimicrobials, antibiotics, or the like.
It is believed that the diffusion or presence of a bioactive agent
can aid in prevention or elimination of bacteria adjacent to the
exit-site. Additionally or alternatively, the bioactive agent can
be integral with or coated on the adhesive layer, or no bioactive
agent at all is employed.
FIG. 4A is an exploded perspective view of the contact subassembly
26 in one embodiment, showing its individual components.
Preferably, a watertight (waterproof or water-resistant) sealing
member 36, also referred to as a sealing material, fits within a
contact holder 34 and provides a watertight seal configured to
surround the electrical connection at the electrode terminals
within the mounting unit in order to protect the electrodes (and
the respective operable connection with the contacts of the
electronics unit 16) from damage due to moisture, humidity, dirt,
and other external environmental factors. In one embodiment, the
sealing member 36 is formed from an elastomeric material, such as
silicone; however, a variety of other elastomeric or sealing
materials can also be used. In alternative embodiments, the seal is
designed to form an interference fit with the electronics unit and
can be formed from a variety of materials, for example, flexible
plastics or noble metals. One of ordinary skill in the art
appreciates that a variety of designs can be employed to provide a
seal surrounding the electrical contacts described herein. For
example, the contact holder 34 can be integrally designed as a part
of the mounting unit, rather than as a separate piece thereof.
Additionally or alternatively, a sealant can be provided in or
around the sensor (e.g., within or on the contact subassembly or
sealing member), such as is described in more detail with reference
to FIGS. 11A and 11B.
In the illustrated embodiment, the sealing member 36 is formed with
a raised portion 37 surrounding the contacts 28. The raised portion
37 enhances the interference fit surrounding the contacts 28 when
the electronics unit 16 is mated to the mounting unit 14. Namely,
the raised portion surrounds each contact and presses against the
electronics unit 16 to form a tight seal around the electronics
unit.
Contacts 28 fit within the seal 36 and provide for electrical
connection between the sensor 32 and the electronics unit 16. In
general, the contacts are designed to ensure a stable mechanical
and electrical connection of the electrodes that form the sensor 32
(see FIG. 5A to 5C) to mutually engaging contacts 28 thereon. A
stable connection can be provided using a variety of known methods,
for example, domed metallic contacts, cantilevered fingers, pogo
pins, or the like, as is appreciated by one skilled in the art.
In preferred embodiments, the contacts 28 are formed from a
conductive elastomeric material, such as a carbon black elastomer,
through which the sensor 32 extends (see FIGS. 10B and 11B).
Conductive elastomers are advantageously employed because their
resilient properties create a natural compression against mutually
engaging contacts, forming a secure press fit therewith. In some
embodiments, conductive elastomers can be molded in such a way that
pressing the elastomer against the adjacent contact performs a
wiping action on the surface of the contact, thereby creating a
cleaning action during initial connection. Additionally, in
preferred embodiments, the sensor 32 extends through the contacts
28 wherein the sensor is electrically and mechanically secure by
the relaxation of elastomer around the sensor (see FIGS. 7A to
7D).
In an alternative embodiment, a conductive, stiff plastic forms the
contacts, which are shaped to comply upon application of pressure
(for example, a leaf-spring shape). Contacts of such a
configuration can be used instead of a metallic spring, for
example, and advantageously avoid the need for crimping or
soldering through compliant materials; additionally, a wiping
action can be incorporated into the design to remove contaminants
from the surfaces during connection. Non-metallic contacts can be
advantageous because of their seamless manufacturability,
robustness to thermal compression, non-corrosive surfaces, and
native resistance to electrostatic discharge (ESD) damage due to
their higher-than-metal resistance.
FIGS. 4B and 4C are perspective views of alternative contact
configurations. FIG. 4B is an illustration of a narrow contact
configuration. FIG. 4C is an illustration of a wide contact
configuration. One skilled in the art appreciates that a variety of
configurations are suitable for the contacts of the preferred
embodiments, whether elastomeric, stiff plastic, or other materials
are used. In some circumstances, it can be advantageous to provide
multiple contact configurations (such as illustrated in FIGS. 4A to
4C) to differentiate sensors from each other. In other words, the
architecture of the contacts can include one or more configurations
each designed (keyed) to fit with a particular electronics unit.
See section entitled "Differentiation of Sensor Systems" below,
which describes systems and methods for differentiating (keying)
sensor systems.
Sensor
Preferably, the sensor 32 includes a distal portion 42, also
referred to as the in vivo portion, adapted to extend out of the
mounting unit for insertion under the host's skin, and a proximal
portion 40, also referred to as an ex vivo portion, adapted to
remain above the host's skin after sensor insertion and to operably
connect to the electronics unit 16 via contacts 28. Preferably, the
sensor 32 includes two or more electrodes: a working electrode 44
and at least one additional electrode, which can function as a
counter electrode and/or reference electrode, hereinafter referred
to as the reference electrode 46. A membrane system is preferably
deposited over the electrodes, such as described in more detail
with reference to FIGS. 5A to 5C, below.
FIG. 5A is an expanded cutaway view of a proximal portion 40 of the
sensor in one embodiment, showing working and reference electrodes.
In the illustrated embodiments, the working and reference
electrodes 44, 46 extend through the contacts 28 to form electrical
connection therewith (see FIGS. 10B and 11B). Namely, the working
electrode 44 is in electrical contact with one of the contacts 28
and the reference electrode 46 is in electrical contact with the
other contact 28, which in turn provides for electrical connection
with the electronics unit 16 when it is mated with the mounting
unit 14. Mutually engaging electrical contacts permit operable
connection of the sensor 32 to the electronics unit 16 when
connected to the mounting unit 14; however other methods of
electrically connecting the electronics unit 16 to the sensor 32
are also possible. In some alternative embodiments, for example,
the reference electrode can be configured to extend from the sensor
and connect to a contact at another location on the mounting unit
(e.g., non-coaxially). Detachable connection between the mounting
unit 14 and electronics unit 16 provides improved
manufacturability, namely, the relatively inexpensive mounting unit
14 can be disposed of when replacing the sensor system after its
usable life, while the relatively more expensive electronics unit
16 can be reused with multiple sensor systems.
In alternative embodiments, the contacts 28 are formed into a
variety of alternative shapes and/or sizes. For example, the
contacts 28 can be discs, spheres, cuboids, and the like.
Furthermore, the contacts 28 can be designed to extend from the
mounting unit in a manner that causes an interference fit within a
mating cavity or groove of the electronics unit, forming a stable
mechanical and electrical connection therewith.
FIG. 5B is an expanded cutaway view of a distal portion of the
sensor in one embodiment, showing working and reference electrodes.
In preferred embodiments, the sensor is formed from a working
electrode 44 and a reference electrode 46 helically wound around
the working electrode 44. An insulator 45 is disposed between the
working and reference electrodes to provide necessary electrical
insulation therebetween. Certain portions of the electrodes are
exposed to enable electrochemical reaction thereon, for example, a
window 43 can be formed in the insulator to expose a portion of the
working electrode 44 for electrochemical reaction.
In preferred embodiments, each electrode is formed from a fine wire
with a diameter of from about 0.001 or less to about 0.010 inches
or more, for example, and is formed from, e.g., a plated insulator,
a plated wire, or bulk electrically conductive material. Although
the illustrated electrode configuration and associated text
describe one preferred method of forming a transcutaneous sensor, a
variety of known transcutaneous sensor configurations can be
employed with the transcutaneous analyte sensor system of the
preferred embodiments, such as are described in U.S. Pat. No.
6,695,860 to Ward et al., U.S. Pat. No. 6,565,509 to Say et al.,
U.S. Pat. No. 6,248,067 to Causey III, et al., and U.S. Pat. No.
6,514,718 to Heller et al.
In preferred embodiments, the working electrode comprises a wire
formed from a conductive material, such as platinum,
platinum-iridium, palladium, graphite, gold, carbon, conductive
polymer, alloys, or the like. Although the electrodes can by formed
by a variety of manufacturing techniques (bulk metal processing,
deposition of metal onto a substrate, or the like), it can be
advantageous to form the electrodes from plated wire (e.g.,
platinum on steel wire) or bulk metal (e.g., platinum wire). It is
believed that electrodes formed from bulk metal wire provide
superior performance (e.g., in contrast to deposited electrodes),
including increased stability of assay, simplified
manufacturability, resistance to contamination (e.g., which can be
introduced in deposition processes), and improved surface reaction
(e.g., due to purity of material) without peeling or
delamination.
The working electrode 44 is configured to measure the concentration
of an analyte. In an enzymatic electrochemical sensor for detecting
glucose, for example, the working electrode measures the hydrogen
peroxide produced by an enzyme catalyzed reaction of the analyte
being detected and creates a measurable electronic current For
example, in the detection of glucose wherein glucose oxidase
produces hydrogen peroxide as a byproduct, hydrogen peroxide reacts
with the surface of the working electrode producing two protons
(2H.sup.+), two electrons (2e.sup.-) and one molecule of oxygen
(O.sub.2), which produces the electronic current being
detected.
In preferred embodiments, the working electrode 44 is covered with
an insulating material 45, for example, a non-conductive polymer.
Dip-coating, spray-coating, vapor-deposition, or other coating or
deposition techniques can be used to deposit the insulating
material on the working electrode. In one embodiment, the
insulating material comprises parylene, which can be an
advantageous polymer coating for its strength, lubricity, and
electrical insulation properties. Generally, parylene is produced
by vapor deposition and polymerization of para-xylylene (or its
substituted derivatives). While not wishing to be bound by theory,
it is believed that the lubricious coating (e.g., parylene) on the
sensors of the preferred embodiments contributes to minimal trauma
and extended sensor life. FIG. 21 shows transcutaneous glucose
sensor data and corresponding blood glucose values over
approximately seven days in a human, wherein the transcutaneous
glucose sensor data was formed with a parylene coating on at least
a portion of the device. While parylene coatings are generally
preferred, any suitable insulating material can be used, for
example, fluorinated polymers, polyethyleneterephthalate,
polyurethane, polyimide, other nonconducting polymers, or the like.
Glass or ceramic materials can also be employed. Other materials
suitable for use include surface energy modified coating systems
such as are marketed under the trade names AMC18, AMC148, AMC141,
and AMC321 by Advanced Materials Components Express of Bellafonte,
Pa. In some alternative embodiments, however, the working electrode
may not require a coating of insulator.
The reference electrode 46, which can function as a reference
electrode alone, or as a dual reference and counter electrode, is
formed from silver, silver/silver chloride, or the like.
Preferably, the reference electrode 46 is juxtapositioned and/or
twisted with or around the working electrode 44; however other
configurations are also possible (e.g., an intradermal or on-skin
reference electrode). In some embodiments, a reference and/or
counter electrode is located in or on the adhesive layer.
In the illustrated embodiments, the reference electrode 46 is
helically wound around the working electrode 44. The assembly of
wires is then optionally coated or adhered together with an
insulating material, similar to that described above, so as to
provide an insulating attachment.
In some embodiments, a silver wire is formed onto the sensor as
described above, and subsequently chloridized to form silver/silver
chloride reference electrode. Advantageously, chloridizing the
silver wire as described herein enables the manufacture of a
reference electrode with optimal in vivo performance. Namely, by
controlling the quantity and amount of chloridization of the silver
to form silver/silver chloride, improved break-in time, stability
of the reference electrode, and extended life has been shown with
the preferred embodiments (see FIGS. 20 and 21). Additionally, use
of silver chloride as described above allows for relatively
inexpensive and simple manufacture of the reference electrode.
In embodiments wherein an outer insulator is disposed, a portion of
the coated assembly structure can be stripped or otherwise removed,
for example, by hand, excimer lasing, chemical etching, laser
ablation, grit-blasting (e.g., with sodium bicarbonate or other
suitable grit), or the like, to expose the electroactive surfaces.
Alternatively, a portion of the electrode can be masked prior to
depositing the insulator in order to maintain an exposed
electroactive surface area. In one exemplary embodiment, grit
blasting is implemented to expose the electroactive surfaces,
preferably utilizing a grit material that is sufficiently hard to
ablate the polymer material, while being sufficiently soft so as to
minimize or avoid damage to the underlying metal electrode (e.g., a
platinum electrode). Although a variety of "grit" materials can be
used (e.g., sand, talc, walnut shell, ground plastic, sea salt, and
the like), in some preferred embodiments, sodium bicarbonate is an
advantageous grit-material because it is sufficiently hard to
ablate, e.g., a parylene coating without damaging, e.g., an
underlying platinum conductor. One additional advantage of sodium
bicarbonate blasting includes its polishing action on the metal as
it strips the polymer layer, thereby eliminating a cleaning step
that might otherwise be necessary.
In the embodiment illustrated in FIG. 5B, a radial window 43 is
formed through the insulating material 45 to expose a
circumferential electroactive surface of the working electrode.
Additionally, sections 41 of electroactive surface of the reference
electrode are exposed. For example, the 41 sections of
electroactive surface can be masked during deposition of an outer
insulating layer or etched after deposition of an outer insulating
layer.
In some applications, cellular attack or migration of cells to the
sensor can cause reduced sensitivity and/or function of the device,
particularly after the first day of implantation. However, when the
exposed electroactive surface is distributed circumferentially
about the sensor (e.g., as in a radial window), the available
surface area for reaction can be sufficiently distributed so as to
minimize the effect of local cellular invasion of the sensor on the
sensor signal. Alternatively, a tangential exposed electroactive
window can be formed, for example, by stripping only one side of
the coated assembly structure. In other alternative embodiments,
the window can be provided at the tip of the coated assembly
structure such that the electroactive surfaces are exposed at the
tip of the sensor. Other methods and configurations for exposing
electroactive surfaces can also be employed.
In some embodiments, the working electrode has a diameter of from
about 0.001 inches or less to about 0.010 inches or more,
preferably from about 0.002 inches to about 0.008 inches, and more
preferably from about 0.004 inches to about 0.005 inches. The
length of the window can be from about 0.1 mm (about 0.004 inches)
or less to about 2 mm (about 0.078 inches) or more, and preferably
from about 0.5 mm (about 0.02 inches) to about 0.75 mm (0.03
inches). In such embodiments, the exposed surface area of the
working electrode is preferably from about 0.000013 in.sup.2
(0.0000839 cm.sup.2) or less to about 0.0025 in.sup.2 (0.016129
cm.sup.2) or more (assuming a diameter of from about 0.001 inches
to about 0.010 inches and a length of from about 0.004 inches to
about 0.078 inches). The preferred exposed surface area of the
working electrode is selected to produce an analyte signal with a
current in the picoAmp range, such as is described in more detail
elsewhere herein. However, a current in the picoAmp range can be
dependent upon a variety of factors, for example the electronic
circuitry design (e.g., sample rate, current draw, A/D converter
bit resolution, etc.), the membrane system (e.g., permeability of
the analyte through the membrane system), and the exposed surface
area of the working electrode. Accordingly, the exposed
electroactive working electrode surface area can be selected to
have a value greater than or less than the above-described ranges
taking into consideration alterations in the membrane system and/or
electronic circuitry. In preferred embodiments of a glucose sensor,
it can be advantageous to minimize the surface area of the working
electrode while maximizing the diffusivity of glucose in order to
optimize the signal-to-noise ratio while maintaining sensor
performance in both high and low glucose concentration ranges.
In some alternative embodiments, the exposed surface area of the
working (and/or other) electrode can be increased by altering the
cross-section of the electrode itself. For example, in some
embodiments the cross-section of the working electrode can be
defined by a cross, star, cloverleaf, ribbed, dimpled, ridged,
irregular, or other non-circular configuration; thus, for any
predetermined length of electrode, a specific increased surface
area can be achieved (as compared to the area achieved by a
circular cross-section). Increasing the surface area of the working
electrode can be advantageous in providing an increased signal
responsive to the analyte concentration, which in turn can be
helpful in improving the signal-to-noise ratio, for example.
In some alternative embodiments, additional electrodes can be
included within the assembly, for example, a three-electrode system
(working, reference, and counter electrodes) and/or an additional
working electrode (e.g., an electrode which can be used to generate
oxygen, which is configured as a baseline subtracting electrode, or
which is configured for measuring additional analytes). U.S. Pat.
No. 7,081,195 and U.S. Patent Publication No. US-2005-0143635-A1
describe some systems and methods for implementing and using
additional working, counter, and/or reference electrodes. In one
implementation wherein the sensor comprises two working electrodes,
the two working electrodes are juxtapositioned (e.g., extend
parallel to each other), around which the reference electrode is
disposed (e.g., helically wound). In some embodiments wherein two
or more working electrodes are provided, the working electrodes can
be formed in a double-, triple-, quad-, etc. helix configuration
along the length of the sensor (for example, surrounding a
reference electrode, insulated rod, or other support structure).
The resulting electrode system can be configured with an
appropriate membrane system, wherein the first working electrode is
configured to measure a first signal comprising glucose and
baseline and the additional working electrode is configured to
measure a baseline signal consisting of baseline only (e.g.,
configured to be substantially similar to the first working
electrode without an enzyme disposed thereon). In this way, the
baseline signal can be subtracted from the first signal to produce
a glucose-only signal that is substantially not subject to
fluctuations in the baseline and/or interfering species on the
signal.
Although the preferred embodiments illustrate one electrode
configuration including one bulk metal wire helically wound around
another bulk metal wire, other electrode configurations are also
contemplated. In an alternative embodiment, the working electrode
comprises a tube with a reference electrode disposed or coiled
inside, including an insulator therebetween. Alternatively, the
reference electrode comprises a tube with a working electrode
disposed or coiled inside, including an insulator therebetween. In
another alternative embodiment, a polymer (e.g., insulating) rod is
provided, wherein the electrodes are deposited (e.g.,
electro-plated) thereon. In yet another alternative embodiment, a
metallic (e.g., steel) rod is provided, coated with an insulating
material, onto which the working and reference electrodes are
deposited. In yet another alternative embodiment, one or more
working electrodes are helically wound around a reference
electrode.
In another alternative embodiment, the reference electrode is
coiled around the working electrode as in the exemplified
embodiment; however the reference electrode extends farther toward
the distal end (i.e., in vivo end) of the sensor than in the
exemplified embodiment. Preferably, the reference electrode extends
(e.g., helically) at least to the exposed working electrode window
and preferably across and/or beyond the exposed working electrode
window toward the sensor tip. While not wishing to be bound by
theory, it is believed that this design enables a reduction in
length of the sensor, provides more surface area for the reference
electrode and/or protects the membrane system from damage caused by
mechanical movement, and the like.
Preferably, the electrodes and membrane systems of the preferred
embodiments are coaxially formed, namely, the electrodes and/or
membrane system all share the same central axis. While not wishing
to be bound by theory, it is believed that a coaxial design of the
sensor enables a symmetrical design without a preferred bend
radius. Namely, in contrast to prior art sensors comprising a
substantially planar configuration that can suffer from regular
bending about the plane of the sensor, the coaxial design of the
preferred embodiments do not have a preferred bend radius and
therefore are not subject to regular bending about a particular
plane (which can cause fatigue failures and the like). However,
non-coaxial sensors can be implemented with the sensor system of
the preferred embodiments.
In addition to the above-described advantages, the coaxial sensor
design of the preferred embodiments enables the diameter of the
connecting end of the sensor (proximal portion) to be substantially
the same as that of the sensing end (distal portion) such that the
needle is able to insert the sensor into the host and subsequently
slide back over the sensor and release the sensor from the needle,
without slots or other complex multi-component designs.
In one such alternative embodiment, the two wires of the sensor are
held apart and configured for insertion into the host in proximal
but separate locations. The separation of the working and reference
electrodes in such an embodiment can provide additional
electrochemical stability with simplified manufacture and
electrical connectivity. It is appreciated by one skilled in the
art that a variety of electrode configurations can be implemented
with the preferred embodiments.
In some embodiments, the sensor includes an antimicrobial portion
configured to extend through the exit-site when the sensor is
implanted in the host. Namely, the sensor is designed with in vivo
and ex vivo portions as described in more detail elsewhere herein;
additionally, the sensor comprises a transition portion, also
referred to as an antimicrobial portion, located between the in
vivo and ex vivo portions 42, 40. The antimicrobial portion is
designed to provide antimicrobial effects to the exit-site and
adjacent tissue when implanted in the host.
In some embodiments, the antimicrobial portion comprises silver,
e.g., the portion of a silver reference electrode that is
configured to extend through the exit-site when implanted. Although
exit-site infections are a common adverse occurrence associated
with some conventional transcutaneous medical devices, the devices
of preferred embodiments are designed at least in part to minimize
infection, to minimize irritation, and/or to extend the duration of
implantation of the sensor by utilizing a silver reference
electrode to extend through the exit-site when implanted in a
patient. While not wishing to be bound by theory, it is believed
that the silver may reduce local tissue infections (within the
tissue and at the exit-site); namely, steady release of molecular
quantities of silver is believed to have an antimicrobial effect in
biological tissue (e.g., reducing or preventing irritation and
infection), also referred to as passive antimicrobial effects.
Although one example of passive antimicrobial effects is described
herein, one skilled in the art can appreciate a variety of passive
anti-microbial systems and methods that can be implemented with the
preferred embodiments. Additionally, it is believed that
antimicrobial effects can contribute to extended life of a
transcutaneous analyte sensor, enabling a functional lifetime past
a few days, e.g., seven days or longer. FIG. 21 shows
transcutaneous glucose sensor data and corresponding blood glucose
values over approximately seven days in a human, wherein the
transcutaneous glucose sensor data was formed with a silver
transition portion that extended through the exit-site after sensor
implantation.
In some embodiments, active antimicrobial systems and methods are
provided in the sensor system in order to further enhance the
antimicrobial effects at the exit-site. In one such embodiment, an
auxiliary silver wire is disposed on or around the sensor, wherein
the auxiliary silver wire is connected to electronics and
configured to pass a current sufficient to enhance its
antimicrobial properties (active antimicrobial effects), as is
appreciated by one skilled in the art. The current can be passed
continuously or intermittently, such that sufficient antimicrobial
properties are provided. Although one example of active
antimicrobial effects is described herein, one skilled in the art
can appreciate a variety of active anti-microbial systems and
methods that can be implemented with the preferred embodiments.
Anchoring Mechanism
It is preferred that the sensor remains substantially stationary
within the tissue of the host, such that migration or motion of the
sensor with respect to the surrounding tissue is minimized.
Migration or motion is believed to cause inflammation at the sensor
implant site due to irritation, and can also cause noise on the
sensor signal due to motion-related artifact, for example.
Therefore, it can be advantageous to provide an anchoring mechanism
that provides support for the sensor's in vivo portion to avoid the
above-mentioned problems. Combining advantageous sensor geometry
with an advantageous anchoring minimizes additional parts and
allows for an optimally small or low profile design of the sensor.
In one embodiment the sensor includes a surface topography, such as
the helical surface topography provided by the reference electrode
surrounding the working electrode. In alternative embodiments, a
surface topography could be provided by a roughened surface, porous
surface (e.g. porous parylene), ridged surface, or the like.
Additionally (or alternatively), the anchoring can be provided by
prongs, spines, barbs, wings, hooks, a bulbous portion (for
example, at the distal end), an S-bend along the sensor, a rough
surface topography, a gradually changing diameter, combinations
thereof, or the like, which can be used alone or in combination
with the helical surface topography to stabilize the sensor within
the subcutaneous tissue.
Variable Stiffness
As described above, conventional transcutaneous devices are
believed to suffer from motion artifact associated with host
movement when the host is using the device. For example, when a
transcutaneous analyte sensor is inserted into the host, various
movements on the sensor (for example, relative movement within and
between the subcutaneous space, dermis, skin, and external portions
of the sensor) create stresses on the device, which is known to
produce artifacts on the sensor signal. Accordingly, there are
different design considerations (for example, stress
considerations) on various sections of the sensor. For example, the
distal portion 42 of the sensor can benefit in general from greater
flexibility as it encounters greater mechanical stresses caused by
movement of the tissue within the patient and relative movement
between the in vivo and ex vivo portions of the sensor. On the
other hand, the proximal portion 40 of the sensor can benefit in
general from a stiffer, more robust design to ensure structural
integrity and/or reliable electrical connections. Additionally, in
some embodiments wherein a needle is retracted over the proximal
portion 40 of the device (see FIGS. 6 to 8), a stiffer design can
minimize crimping of the sensor and/or ease in retraction of the
needle from the sensor. Thus, by designing greater flexibility into
the in vivo (distal) portion 42, the flexibility is believed to
compensate for patient movement, and noise associated therewith. By
designing greater stiffness into the ex vivo (proximal) portion 40,
column strength (for retraction of the needle over the sensor),
electrical connections, and integrity can be enhanced. In some
alternative embodiments, a stiffer distal end and/or a more
flexible proximal end can be advantageous as described in U.S.
Patent Publication No. US-2006-0015024-A1.
The preferred embodiments provide a distal portion 42 of the sensor
32 designed to be more flexible than a proximal portion 40 of the
sensor. The variable stiffness of the preferred embodiments can be
provided by variable pitch of any one or more helically wound wires
of the device, variable cross-section of any one or more wires of
the device, and/or variable hardening and/or softening of any one
or more wires of the device, such as is described in more detail
with reference to U.S. Patent Publication No.
US-2006-0015024-A1.
Membrane System
FIG. 5C is a cross-sectional view through the sensor on line C-C of
FIG. 5B showing the exposed electroactive surface of the working
electrode surrounded by the membrane system in one embodiment.
Preferably, a membrane system is deposited over at least a portion
of the electroactive surfaces of the sensor 32 (working electrode
and optionally reference electrode) and provides protection of the
exposed electrode surface from the biological environment,
diffusion resistance (limitation) of the analyte if needed, a
catalyst for enabling an enzymatic reaction, limitation or blocking
of interferants, and/or hydrophilicity at the electrochemically
reactive surfaces of the sensor interface. Some examples of
suitable membrane systems are described in U.S. Patent Publication
No. US-2005-0245799-A1.
In general, the membrane system includes a plurality of domains,
for example, an electrode domain 47, an interference domain 48, an
enzyme domain 49 (for example, including glucose oxidase), and a
resistance domain 50, and can include a high oxygen solubility
domain, and/or a bioprotective domain (not shown), such as is
described in more detail in U.S. Patent Publication No.
US-2005-0245799-A1, and such as is described in more detail below.
The membrane system can be deposited on the exposed electroactive
surfaces using known thin film techniques (for example, spraying,
electro-depositing, dipping, or the like). In one embodiment, one
or more domains are deposited by dipping the sensor into a solution
and drawing out the sensor at a speed that provides the appropriate
domain thickness. However, the membrane system can be disposed over
(or deposited on) the electroactive surfaces using any known method
as will be appreciated by one skilled in the art.
Electrode Domain
In some embodiments, the membrane system comprises an optional
electrode domain 47. The electrode domain 47 is provided to ensure
that an electrochemical reaction occurs between the electroactive
surfaces of the working electrode and the reference electrode, and
thus the electrode domain 47 is preferably situated more proximal
to the electroactive surfaces than the enzyme domain. Preferably,
the electrode domain 47 includes a semipermeable coating that
maintains a layer of water at the electrochemically reactive
surfaces of the sensor, for example, a humectant in a binder
material can be employed as an electrode domain; this allows for
the full transport of ions in the aqueous environment. The
electrode domain can also assist in stabilizing the operation of
the sensor by overcoming electrode start-up and drifting problems
caused by inadequate electrolyte. The material that forms the
electrode domain can also protect against pH-mediated damage that
can result from the formation of a large pH gradient due to the
electrochemical activity of the electrodes.
In one embodiment, the electrode domain 47 includes a flexible,
water-swellable, hydrogel film having a "dry film" thickness of
from about 0.05 micron or less to about 20 microns or more, more
preferably from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4,
0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 to about 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more
preferably from about 2, 2.5 or 3 microns to about 3.5, 4, 4.5, or
5 microns. "Dry film" thickness refers to the thickness of a cured
film cast from a coating formulation by standard coating
techniques.
In certain embodiments, the electrode domain 47 is formed of a
curable mixture of a urethane polymer and a hydrophilic polymer.
Particularly preferred coatings are formed of a polyurethane
polymer having carboxylate functional groups and non-ionic
hydrophilic polyether segments, wherein the polyurethane polymer is
crosslinked with a water soluble carbodiimide (e.g.,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC))) in the
presence of polyvinylpyrrolidone and cured at a moderate
temperature of about 50.degree. C.
Preferably, the electrode domain 47 is deposited by spray or
dip-coating the electroactive surfaces of the sensor 32. More
preferably, the electrode domain is formed by dip-coating the
electroactive surfaces in an electrode solution and curing the
domain for a time of from about 15 to about 30 minutes at a
temperature of from about 40 to about 55.degree. C. (and can be
accomplished under vacuum (e.g., 20 to 30 mmHg)). In embodiments
wherein dip-coating is used to deposit the electrode domain, a
preferred insertion rate of from about 1 to about 3 inches per
minute, with a preferred dwell time of from about 0.5 to about 2
minutes, and a preferred withdrawal rate of from about 0.25 to
about 2 inches per minute provide a functional coating. However,
values outside of those set forth above can be acceptable or even
desirable in certain embodiments, for example, dependent upon
viscosity and surface tension as is appreciated by one skilled in
the art. In one embodiment, the electroactive surfaces of the
electrode system are dip-coated one time (one layer) and cured at
50.degree. C. under vacuum for 20 minutes.
Although an independent electrode domain is described herein, in
some embodiments, sufficient hydrophilicity can be provided in the
interference domain and/or enzyme domain (the domain adjacent to
the electroactive surfaces) so as to provide for the full transport
of ions in the aqueous environment (e.g. without a distinct
electrode domain).
Interference Domain
In some embodiments, an optional interference domain 48 is
provided, which generally includes a polymer domain that restricts
the flow of one or more interferants. In some embodiments, the
interference domain 48 functions as a molecular sieve that allows
analytes and other substances that are to be measured by the
electrodes to pass through, while preventing passage of other
substances, including interferants such as ascorbate and urea (see
U.S. Pat. No. 6,001,067 to Shults). Some known interferants for a
glucose-oxidase based electrochemical sensor include acetaminophen,
ascorbic acid, bilirubin, cholesterol, creatinine, dopamine,
ephedrine, ibuprofen, L-dopa, methyldopa, salicylate, tetracycline,
tolazamide, tolbutamide, triglycerides, and uric acid.
Several polymer types that can be utilized as a base material for
the interference domain 48 include polyurethanes, polymers having
pendant ionic groups, and polymers having controlled pore size, for
example. In one embodiment, the interference domain includes a
thin, hydrophobic membrane that is non-swellable and restricts
diffusion of low molecular weight species. The interference domain
48 is permeable to relatively low molecular weight substances, such
as hydrogen peroxide, but restricts the passage of higher molecular
weight substances, including glucose and ascorbic acid. Other
systems and methods for reducing or eliminating interference
species that can be applied to the membrane system of the preferred
embodiments are described in U.S. Pat. No. 7,074,307, U.S. Patent
Publication No. US-2005-0176136-A1, U.S. Pat. No. 7,081,195, and
U.S. Patent Publication No. US-2005-0143635-A1. In some alternative
embodiments, a distinct interference domain is not included.
In preferred embodiments, the interference domain 48 is deposited
onto the electrode domain (or directly onto the electroactive
surfaces when a distinct electrode domain is not included) for a
domain thickness of from about 0.05 micron or less to about 20
microns or more, more preferably from about 0.05, 0.1, 0.15, 0.2,
0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 to about
4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5
microns, and more preferably from about 2, 2.5 or 3 microns to
about 3.5, 4, 4.5, or 5 microns. Thicker membranes can also be
useful, but thinner membranes are generally preferred because they
have a lower impact on the rate of diffusion of hydrogen peroxide
from the enzyme membrane to the electrodes. Unfortunately, the thin
thickness of the interference domains conventionally used can
introduce variability in the membrane system processing. For
example, if too much or too little interference domain is
incorporated within a membrane system, the performance of the
membrane can be adversely affected.
Enzyme Domain
In preferred embodiments, the membrane system further includes an
enzyme domain 49 disposed more distally situated from the
electroactive surfaces than the interference domain 48 (or
electrode domain 47 when a distinct interference is not included).
In some embodiments, the enzyme domain is directly deposited onto
the electroactive surfaces (when neither an electrode or
interference domain is included). In the preferred embodiments, the
enzyme domain 49 provides an enzyme to catalyze the reaction of the
analyte and its co-reactant, as described in more detail below.
Preferably, the enzyme domain includes glucose oxidase; however
other oxidases, for example, galactose oxidase or uricase oxidase,
can also be used.
For an enzyme-based electrochemical glucose sensor to perform well,
the sensor's response is preferably limited by neither enzyme
activity nor co-reactant concentration. Because enzymes, including
glucose oxidase, are subject to deactivation as a function of time
even in ambient conditions, this behavior is compensated for in
forming the enzyme domain. Preferably, the enzyme domain 49 is
constructed of aqueous dispersions of colloidal polyurethane
polymers including the enzyme. However, in alternative embodiments
the enzyme domain is constructed from an oxygen enhancing material,
for example, silicone or fluorocarbon, in order to provide a supply
of excess oxygen during transient ischemia. Preferably, the enzyme
is immobilized within the domain. See U.S. Patent Publication No.
US-2005-0054909-A1.
In preferred embodiments, the enzyme domain 49 is deposited onto
the interference domain for a domain thickness of from about 0.05
micron or less to about 20 microns or more, more preferably from
about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1,
1.5, 2, 2.5, 3, or 3.5 to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19, or 19.5 microns, and more preferably from
about 2, 2.5 or 3 microns to about 3.5, 4, 4.5, or 5 microns.
However in some embodiments, the enzyme domain is deposited onto
the electrode domain or directly onto the electroactive surfaces.
Preferably, the enzyme domain 49 is deposited by spray or dip
coating. More preferably, the enzyme domain is formed by
dip-coating the electrode domain into an enzyme domain solution and
curing the domain for from about 15 to about 30 minutes at a
temperature of from about 40 to about 55.degree. C. (and can be
accomplished under vacuum (e.g., 20 to 30 mmHg)). In embodiments
wherein dip-coating is used to deposit the enzyme domain at room
temperature, a preferred insertion rate of from about 1 inch per
minute to about 3 inches per minute, with a preferred dwell time of
from about 0.5 minutes to about 2 minutes, and a preferred
withdrawal rate of from about 0.25 inch per minute to about 2
inches per minute provide a functional coating. However, values
outside of those set forth above can be acceptable or even
desirable in certain embodiments, for example, dependent upon
viscosity and surface tension as is appreciated by one skilled in
the art. In one embodiment, the enzyme domain 49 is formed by dip
coating two times (namely, forming two layers) in a coating
solution and curing at 50.degree. C. under vacuum for 20 minutes.
However, in some embodiments, the enzyme domain can be formed by
dip-coating and/or spray-coating one or more layers at a
predetermined concentration of the coating solution, insertion
rate, dwell time, withdrawal rate, and/or desired thickness.
Resistance Domain
In preferred embodiments, the membrane system includes a resistance
domain 50 disposed more distal from the electroactive surfaces than
the enzyme domain 49. Although the following description is
directed to a resistance domain for a glucose sensor, the
resistance domain can be modified for other analytes and
co-reactants as well.
There exists a molar excess of glucose relative to the amount of
oxygen in blood; that is, for every free oxygen molecule in
extracellular fluid, there are typically more than 100 glucose
molecules present (see Updike et al., Diabetes Care
5:207-21(1982)). However, an immobilized enzyme-based glucose
sensor employing oxygen as co-reactant is preferably supplied with
oxygen in non-rate-limiting excess in order for the sensor to
respond linearly to changes in glucose concentration, while not
responding to changes in oxygen concentration. Specifically, when a
glucose-monitoring reaction is oxygen limited, linearity is not
achieved above minimal concentrations of glucose. Without a
semipermeable membrane situated over the enzyme domain to control
the flux of glucose and oxygen, a linear response to glucose levels
can be obtained only for glucose concentrations of up to about 40
mg/dL. However, in a clinical setting, a linear response to glucose
levels is desirable up to at least about 400 mg/dL.
The resistance domain 50 includes a semi permeable membrane that
controls the flux of oxygen and glucose to the underlying enzyme
domain 49, preferably rendering oxygen in a non-rate-limiting
excess. As a result, the upper limit of linearity of glucose
measurement is extended to a much higher value than that which is
achieved without the resistance domain. In one embodiment, the
resistance domain 50 exhibits an oxygen to glucose permeability
ratio of from about 50:1 or less to about 400:1 or more, preferably
about 200:1. As a result, one-dimensional reactant diffusion is
adequate to provide excess oxygen at all reasonable glucose and
oxygen concentrations found in the subcutaneous matrix (See Rhodes
et al., Anal. Chem., 66:1520-1529 (1994)).
In alternative embodiments, a lower ratio of oxygen-to-glucose can
be sufficient to provide excess oxygen by using a high oxygen
solubility domain (for example, a silicone or fluorocarbon-based
material or domain) to enhance the supply/transport of oxygen to
the enzyme domain 49. If more oxygen is supplied to the enzyme,
then more glucose can also be supplied to the enzyme without
creating an oxygen rate-limiting excess. In alternative
embodiments, the resistance domain is formed from a silicone
composition, such as is described in U.S. Patent Publication No.
US-2005-0090607-A1.
In a preferred embodiment, the resistance domain 50 includes a
polyurethane membrane with both hydrophilic and hydrophobic regions
to control the diffusion of glucose and oxygen to an analyte
sensor, the membrane being fabricated easily and reproducibly from
commercially available materials. A suitable hydrophobic polymer
component is a polyurethane, or polyetherurethaneurea. Polyurethane
is a polymer produced by the condensation reaction of a
diisocyanate and a difunctional hydroxyl-containing material. A
polyurethaneurea is a polymer produced by the condensation reaction
of a diisocyanate and a difunctional amine-containing material.
Preferred diisocyanates include aliphatic diisocyanates containing
from about 4 to about 8 methylene units. Diisocyanates containing
cycloaliphatic moieties can also be useful in the preparation of
the polymer and copolymer components of the membranes of preferred
embodiments. The material that forms the basis of the hydrophobic
matrix of the resistance domain can be any of those known in the
art as appropriate for use as membranes in sensor devices and as
having sufficient permeability to allow relevant compounds to pass
through it, for example, to allow an oxygen molecule to pass
through the membrane from the sample under examination in order to
reach the active enzyme or electrochemical electrodes. Examples of
materials which can be used to make non-polyurethane type membranes
include vinyl polymers, polyethers, polyesters, polyamides,
inorganic polymers such as polysiloxanes and polycarbosiloxanes,
natural polymers such as cellulosic and protein based materials,
and mixtures or combinations thereof.
In a preferred embodiment, the hydrophilic polymer component is
polyethylene oxide. For example, one useful hydrophobic-hydrophilic
copolymer component is a polyurethane polymer that includes about
20% hydrophilic polyethylene oxide. The polyethylene oxide portions
of the copolymer are thermodynamically driven to separate from the
hydrophobic portions of the copolymer and the hydrophobic polymer
component. The 20% polyethylene oxide-based soft segment portion of
the copolymer used to form the final blend affects the water
pick-up and subsequent glucose permeability of the membrane.
In preferred embodiments, the resistance domain 50 is deposited
onto the enzyme domain 49 to yield a domain thickness of from about
0.05 microns or less to about 20 microns or more, more preferably
from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5,
1, 1.5, 2, 2.5, 3, or 3.5 to about 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more preferably
from about 2, 2.5, or 3 microns to about 3.5, 4, 4.5, or 5 microns.
Preferably, the resistance domain is deposited onto the enzyme
domain by spray coating or dip coating. In certain embodiments,
spray coating is the preferred deposition technique. The spraying
process atomizes and mists the solution, and therefore most or all
of the solvent is evaporated prior to the coating material settling
on the underlying domain, thereby minimizing contact of the solvent
with the enzyme. One additional advantage of spray-coating the
resistance domain as described in the preferred embodiments
includes formation of a membrane system that substantially blocks
or resists ascorbate (a known electrochemical interferant in
hydrogen peroxide-measuring glucose sensors). While not wishing to
be bound by theory, it is believed that during the process of
depositing the resistance domain as described in the preferred
embodiments, a structural morphology is formed, characterized in
that ascorbate does not substantially permeate therethrough.
In preferred embodiments, the resistance domain 50 is deposited on
the enzyme domain 49 by spray-coating a solution of from about 1
wt. % to about 5 wt. % polymer and from about 95 wt. % to about 99
wt. % solvent. In spraying a solution of resistance domain
material, including a solvent, onto the enzyme domain, it is
desirable to mitigate or substantially reduce any contact with
enzyme of any solvent in the spray solution that can deactivate the
underlying enzyme of the enzyme domain 49. Tetrahydrofuran (THF) is
one solvent that minimally or negligibly affects the enzyme of the
enzyme domain upon spraying. Other solvents can also be suitable
for use, as is appreciated by one skilled in the art.
Although a variety of spraying or deposition techniques can be
used, spraying the resistance domain material and rotating the
sensor at least one time by 180.degree. can provide adequate
coverage by the resistance domain. Spraying the resistance domain
material and rotating the sensor at least two times by 120 degrees
provides even greater coverage (one layer of 360.degree. coverage),
thereby ensuring resistivity to glucose, such as is described in
more detail above.
In preferred embodiments, the resistance domain 50 is spray-coated
and subsequently cured for a time of from about 15 to about 90
minutes at a temperature of from about 40 to about 60.degree. C.
(and can be accomplished under vacuum (e.g., 20 to 30 mmHg)). A
cure time of up to about 90 minutes or more can be advantageous to
ensure complete drying of the resistance domain. While not wishing
to be bound by theory, it is believed that complete drying of the
resistance domain aids in stabilizing the sensitivity of the
glucose sensor signal. It reduces drifting of the signal
sensitivity over time, and complete drying is believed to stabilize
performance of the glucose sensor signal in lower oxygen
environments.
In one embodiment, the resistance domain 50 is formed by
spray-coating at least six layers (namely, rotating the sensor
seventeen times by 120.degree. for at least six layers of
360.degree. coverage) and curing at 50.degree. C. under vacuum for
60 minutes. However, the resistance domain can be formed by
dip-coating or spray-coating any layer or plurality of layers,
depending upon the concentration of the solution, insertion rate,
dwell time, withdrawal rate, and/or the desired thickness of the
resulting film.
Advantageously, sensors with the membrane system of the preferred
embodiments, including an electrode domain 47 and/or interference
domain 48, an enzyme domain 49, and a resistance domain 50, provide
stable signal response to increasing glucose levels of from about
40 to about 400 mg/dL, and sustained function (at least 90% signal
strength) even at low oxygen levels (for example, at about 0.6 mg/L
O.sub.2). While not wishing to be bound by theory, it is believed
that the resistance domain provides sufficient resistivity, or the
enzyme domain provides sufficient enzyme, such that oxygen
limitations are seen at a much lower concentration of oxygen as
compared to prior art sensors.
In preferred embodiments, a sensor signal with a current in the
picoAmp range is preferred, which is described in more detail
elsewhere herein. However, the ability to produce a signal with a
current in the picoAmp range can be dependent upon a combination of
factors, including the electronic circuitry design (e.g., A/D
converter, bit resolution, and the like), the membrane system
(e.g., permeability of the analyte through the resistance domain,
enzyme concentration, and/or electrolyte availability to the
electrochemical reaction at the electrodes), and the exposed
surface area of the working electrode. For example, the resistance
domain can be designed to be more or less restrictive to the
analyte depending upon to the design of the electronic circuitry,
membrane system, and/or exposed electroactive surface area of the
working electrode.
Accordingly, in preferred embodiments, the membrane system is
designed with a sensitivity of from about 1 pA/mg/dL to about 100
pA/mg/dL, preferably from about 5 pA/mg/dL to about 25 pA/mg/dL,
and more preferably from about 4 pA/mg/dL to about 7 pA/mg/dL.
While not wishing to be bound by any particular theory, it is
believed that membrane systems designed with a sensitivity in the
preferred ranges permit measurement of the analyte signal in low
analyte and/or low oxygen situations. Namely, conventional analyte
sensors have shown reduced measurement accuracy in low analyte
ranges due to lower availability of the analyte to the sensor
and/or have shown increased signal noise in high analyte ranges due
to insufficient oxygen necessary to react with the amount of
analyte being measured. While not wishing to be bound by theory, it
is believed that the membrane systems of the preferred embodiments,
in combination with the electronic circuitry design and exposed
electrochemical reactive surface area design, support measurement
of the analyte in the picoAmp range, which enables an improved
level of resolution and accuracy in both low and high analyte
ranges not seen in the prior art.
Mutarotase Enzyme
In some embodiments, mutarotase, an enzyme that converts .alpha.
D-glucose to .beta. D-glucose, is incorporated into the membrane
system. Mutarotase can be incorporated into the enzyme domain
and/or can be incorporated into another domain of the membrane
system. In general, glucose exists in two distinct isomers, .alpha.
and .beta., which are in equilibrium with one another in solution
and in the blood or interstitial fluid. At equilibrium, a is
present at a relative concentration of about 35.5% and .beta. is
present in the relative concentration of about 64.5% (see Okuda et.
al., Anal Biochem. 1971 September; 43(1):312-5). Glucose oxidase,
which is a conventional enzyme used to react with glucose in
glucose sensors, reacts with .beta. D-glucose and not with .alpha.
D-glucose. Since only the .beta. D-glucose isomer reacts with the
glucose oxidase, errant readings may occur in a glucose sensor
responsive to a shift of the equilibrium between the .alpha.
D-glucose and the .beta. D-glucose. Many compounds, such as
calcium, can affect equilibrium shifts of .alpha. D-glucose and
.beta. D-glucose. For example, as disclosed in U.S. Pat. No.
3,964,974 to Banaugh et al., compounds that exert a mutarotation
accelerating effect on a D-glucose include histidine, aspartic
acid, imidazole, glutamic acid, a hydroxyl pyridine, and
phosphate.
Accordingly, a shift in .alpha. D-glucose and .beta. D-glucose
equilibrium can cause a glucose sensor based on glucose oxidase to
err high or low. To overcome the risks associated with errantly
high or low sensor readings due to equilibrium shifts, the sensor
of the preferred embodiments can be configured to measure total
glucose in the host, including .alpha. D-glucose and .beta.
D-glucose by the incorporation of the mutarotase enzyme, which
converts .alpha. D-glucose to .beta. D-glucose.
Although sensors of some embodiments described herein include an
optional interference domain in order to block or reduce one or
more interferants, sensors with the membrane systems of the
preferred embodiments, including an electrode domain 47, an enzyme
domain 48, and a resistance domain 49, have been shown to inhibit
ascorbate without an additional interference domain. Namely, the
membrane system of the preferred embodiments, including an
electrode domain 47, an enzyme domain 48, and a resistance domain
49, has been shown to be substantially non-responsive to ascorbate
in physiologically acceptable ranges. While not wishing to be bound
by theory, it is believed that the processing process of spraying
the depositing the resistance domain by spray coating, as described
herein, forms results in a structural morphology that is
substantially resistance resistant to ascorbate.
Interference-Free Membrane Systems
In general, it is believed that appropriate solvents and/or
deposition methods can be chosen for one or more of the domains of
the membrane system that form one or more transitional domains such
that interferants do not substantially permeate therethrough. Thus,
sensors can be built without distinct or deposited interference
domains, which are non-responsive to interferants. While not
wishing to be bound by theory, it is believed that a simplified
multilayer membrane system, more robust multilayer manufacturing
process, and reduced variability caused by the thickness and
associated oxygen and glucose sensitivity of the deposited
micron-thin interference domain can be provided. Additionally, the
optional polymer-based interference domain, which usually inhibits
hydrogen peroxide diffusion, is eliminated, thereby enhancing the
amount of hydrogen peroxide that passes through the membrane
system.
Oxygen Conduit
As described above, certain sensors depend upon an enzyme within
the membrane system through which the host's bodily fluid passes
and in which the analyte (for example, glucose) within the bodily
fluid reacts in the presence of a co-reactant (for example, oxygen)
to generate a product. The product is then measured using
electrochemical methods, and thus the output of an electrode system
functions as a measure of the analyte. For example, when the sensor
is a glucose oxidase based glucose sensor, the species measured at
the working electrode is H.sub.2O.sub.2. An enzyme, glucose
oxidase, catalyzes the conversion of oxygen and glucose to hydrogen
peroxide and gluconate according to the following reaction:
Glucose+O.sub.2.fwdarw.Gluconate+H.sub.2O.sub.2
Because for each glucose molecule reacted there is a proportional
change in the product, H.sub.2O.sub.2, one can monitor the change
in H.sub.2O.sub.2 to determine glucose concentration. Oxidation of
H.sub.2O.sub.2 by the working electrode is balanced by reduction of
ambient oxygen, enzyme generated H.sub.2O.sub.2 and other reducible
species at a counter electrode, for example. See Fraser, D. M., "An
Introduction to In Vivo Biosensing: Progress and Problems." In
"Biosensors and the Body," D. M. Fraser, ed., 1997, pp. 1-56 John
Wiley and Sons, New York))
In vivo, glucose concentration is generally about one hundred times
or more that of the oxygen concentration. Consequently, oxygen is a
limiting reactant in the electrochemical reaction, and when
insufficient oxygen is provided to the sensor, the sensor is unable
to accurately measure glucose concentration. Thus, depressed sensor
function or inaccuracy is believed to be a result of problems in
availability of oxygen to the enzyme and/or electroactive
surface(s).
Accordingly, in an alternative embodiment, an oxygen conduit (for
example, a high oxygen solubility domain formed from silicone or
fluorochemicals) is provided that extends from the ex vivo portion
of the sensor to the in vivo portion of the sensor to increase
oxygen availability to the enzyme. The oxygen conduit can be formed
as a part of the coating (insulating) material or can be a separate
conduit associated with the assembly of wires that forms the
sensor.
Porous Biointerface Materials
In alternative embodiments, the distal portion 42 includes a porous
material disposed over some portion thereof, which modifies the
host's tissue response to the sensor. In some embodiments, the
porous material surrounding the sensor advantageously enhances and
extends sensor performance and lifetime in the short term by
slowing or reducing cellular migration to the sensor and associated
degradation that would otherwise be caused by cellular invasion if
the sensor were directly exposed to the in vivo environment.
Alternatively, the porous material can provide stabilization of the
sensor via tissue ingrowth into the porous material in the long
term. Suitable porous materials include silicone,
polytetrafluoroethylene, expanded polytetrafluoroethylene,
polyethylene-co-tetrafluoroethylene, polyolefin, polyester,
polycarbonate, biostable polytetrafluoroethylene, homopolymers,
copolymers, terpolymers of polyurethanes, polypropylene (PP),
polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polyvinyl
alcohol (PVA), polybutylene terephthalate (PBT),
polymethylmethacrylate (PMMA), polyether ether ketone (PEEK),
polyamides, polyurethanes, cellulosic polymers, polysulfones and
block copolymers thereof including, for example, di-block,
tri-block, alternating, random and graft copolymers, as well as
metals, ceramics, cellulose, hydrogel polymers, poly
(2-hydroxyethyl methacrylate, pHEMA), hydroxyethyl methacrylate,
(HEMA), polyacrylonitrile-polyvinyl chloride (PAN-PVC), high
density polyethylene, acrylic copolymers, nylon, polyvinyl
difluoride, polyanhydrides, poly(l-lysine), poly (L-lactic acid),
hydroxyethylmethacrylate, hydroxyapeptite, alumina, zirconia,
carbon fiber, aluminum, calcium phosphate, titanium, titanium
alloy, nintinol, stainless steel, and CoCr alloy, or the like, such
as are described in U.S. Patent Publication No. US-2005-0031689-A1
and U.S. Pat. No. 7,192,450.
In some embodiments, the porous material surrounding the sensor
provides unique advantages in the short term (e.g., one to 14 days)
that can be used to enhance and extend sensor performance and
lifetime. However, such materials can also provide advantages in
the long term too (e.g., greater than 14 days). Particularly, the
in vivo portion of the sensor (the portion of the sensor that is
implanted into the host's tissue) is encased (partially or fully)
in a porous material. The porous material can be wrapped around the
sensor (for example, by wrapping the porous material around the
sensor or by inserting the sensor into a section of porous material
sized to receive the sensor). Alternately, the porous material can
be deposited on the sensor (for example, by electrospinning of a
polymer directly thereon). In yet other alternative embodiments,
the sensor is inserted into a selected section of porous
biomaterial. Other methods for surrounding the in vivo portion of
the sensor with a porous material can also be used as is
appreciated by one skilled in the art.
The porous material surrounding the sensor advantageously slows or
reduces cellular migration to the sensor and associated degradation
that would otherwise be caused by cellular invasion if the sensor
were directly exposed to the in vivo environment. Namely, the
porous material provides a barrier that makes the migration of
cells towards the sensor more tortuous and therefore slower
(providing short term advantages). It is believed that this reduces
or slows the sensitivity loss normally observed in a short-term
sensor over time.
In an embodiment wherein the porous material is a high oxygen
solubility material, such as porous silicone, the high oxygen
solubility porous material surrounds some of or the entire in vivo
portion 42 of the sensor. High oxygen solubility materials are
materials that dynamically retain a high availability of oxygen
that can be used to compensate for the local oxygen deficit during
times of transient ischemia (e.g., silicone and fluorocarbons). It
is believed that some signal noise normally seen by a conventional
sensor can be attributed to an oxygen deficit. In one exemplary
embodiment, porous silicone surrounds the sensor and thereby
effectively increases the concentration of oxygen local (proximal)
to the sensor. Thus, an increase in oxygen availability proximal to
the sensor as achieved by this embodiment ensures that an excess of
oxygen over glucose is provided to the sensor; thereby reducing the
likelihood of oxygen limited reactions therein. Accordingly, by
providing a high oxygen solubility material (e.g., porous silicone)
surrounding the in vivo portion of the sensor, it is believed that
increased oxygen availability, reduced signal noise, longevity, and
ultimately enhanced sensor performance can be achieved.
Bioactive Agents
In some alternative embodiments, a bioactive agent is incorporated
into the above described porous material and/or membrane system,
such as is described in U.S. Patent Publication No.
US-2005-0031689-A1, which diffuses out into the environment
adjacent to the sensing region. Additionally or alternately, a
bioactive agent can be administered locally at the exit-site or
implantation-site. Suitable bioactive agents are those that modify
the host's tissue response to the sensor, for example
anti-inflammatory agents, anti-infective agents, anesthetics,
inflammatory agents, growth factors, immunosuppressive agents,
antiplatelet agents, anti-coagulants, anti-proliferates, ACE
inhibitors, cytotoxic agents, anti-barrier cell compounds,
vascularization-inducing compounds, anti-sense molecules, or
mixtures thereof, such as are described in more detail in U.S.
Patent Publication No. US-2005-0031689-A1.
In embodiments wherein the porous material is designed to enhance
short-term (e.g., between about 1 and 14 days) lifetime or
performance of the sensor, a suitable bioactive agent can be chosen
to ensure that tissue ingrowth does not substantially occur within
the pores of the porous material. Namely, by providing a tissue
modifying bioactive agent, such as an anti-inflammatory agent (for
example, Dexamethasone), substantially tissue ingrowth can be
inhibited, at least in the short term, in order to maintain
sufficient glucose transport through the pores of the porous
material to maintain a stable sensitivity.
In embodiments wherein the porous material is designed to enhance
long-term (e.g., between about a day to a year or more) lifetime or
performance of the sensor, a suitable bioactive agent, such as a
vascularization-inducing compound or anti-barrier cell compound,
can be chosen to encourage tissue ingrowth without barrier cell
formation.
In some alternative embodiments, the in vivo portion of the sensor
is designed with porosity therethrough, for example, a design
wherein the sensor wires are configured in a mesh, loose helix
configuration (namely, with spaces between the wires), or with
micro-fabricated holes therethrough. Porosity within the sensor
modifies the host's tissue response to the sensor, because tissue
ingrowth into and/or through the in vivo portion of the sensor
increases stability of the sensor and/or improves host acceptance
of the sensor, thereby extending the lifetime of the sensor in
vivo.
In some alternative embodiments, the sensor is manufactured
partially or wholly using a continuous reel-to-reel process,
wherein one or more manufacturing steps are automated. In such
embodiments, a manufacturing process can be provided substantially
without the need for manual mounting and fixing steps and
substantially without the need human interaction. A process can be
utilized wherein a plurality of sensors of the preferred
embodiments, including the electrodes, insulator, and membrane
system, are continuously manufactured in a semi-automated or
automated process.
In one embodiment, a plurality of twisted pairs is continuously
formed into a coil, wherein a working electrode is coated with an
insulator material around which a plurality of reference electrodes
is wound. The plurality of twisted pairs are preferably indexed and
subsequently moved from one station to the next whereby the
membrane system is serially deposited according to the preferred
embodiments. Preferably, the coil is continuous and remains as such
during the entire sensor fabrication process, including winding of
the electrodes, insulator application, and membrane coating
processes. After drying of the membrane system, each individual
sensor is cut from the continuous coil.
A continuous reel-to-reel process for manufacturing the sensor
eliminates possible sensor damage due to handling by eliminating
handling steps, and provides faster manufacturing due to faster
trouble shooting by isolation when a product fails. Additionally, a
process run can be facilitated because of elimination of steps that
would otherwise be required (e.g., steps in a manual manufacturing
process). Finally, increased or improved product consistency due to
consistent processes within a controlled environment can be
achieved in a machine or robot driven operation.
In one alternative embodiment, a continuous manufacturing process
is contemplated that utilizes physical vapor deposition in a vacuum
to form the sensor. Physical vapor deposition can be used to coat
one or more insulating layers onto the electrodes, and further can
be used to deposit the membrane system thereon. While not wishing
to be bound by theory, it is believed that by implementing physical
vapor deposition to form some portions or the entire sensor of the
preferred embodiments, simplified manufacturing, consistent
deposition, and overall increased reproducibility can be
achieved.
Applicator
FIG. 6 is an exploded side view of an applicator, showing the
components that enable sensor and needle insertion. In this
embodiment, the applicator 12 includes an applicator body 18 that
aides in aligning and guiding the applicator components.
Preferably, the applicator body 18 includes an applicator body base
60 that matingly engages the mounting unit 14 and an applicator
body cap 62 that enables appropriate relationships (for example,
stops) between the applicator components.
The guide tube subassembly 20 includes a guide tube carrier 64 and
a guide tube 66. In some embodiments, the guide tube is a cannula.
The guide tube carrier 64 slides along the applicator body 18 and
maintains the appropriate relative position of the guide tube 66
during insertion and subsequent retraction. For example, prior to
and during insertion of the sensor, the guide tube 66 extends
through the contact subassembly 26 to maintain an opening that
enables easy insertion of the needle therethrough (see FIGS. 7A to
7D). During retraction of the sensor, the guide tube subassembly 20
is pulled back, engaging with and causing the needle and associated
moving components to retract back into the applicator 12 (See FIGS.
7C and 7D).
A needle subassembly 68 is provided that includes a needle carrier
70 and needle 72. The needle carrier 70 cooperates with the other
applicator components and carries the needle 72 between its
extended and retracted positions. The needle can be of any
appropriate size that can encompass the sensor 32 and aid in its
insertion into the host. Preferred sizes include from about 32
gauge or less to about 18 gauge or more, more preferably from about
28 gauge to about 25 gauge, to provide a comfortable insertion for
the host. Referring to the inner diameter of the needle,
approximately 0.006 inches to approximately 0.023 inches is
preferable, and 0.013 inches is most preferable. The needle carrier
70 is configured to engage with the guide tube carrier 64, while
the needle 72 is configured to slidably nest within the guide tube
66, which allows for easy guided insertion (and retraction) of the
needle through the contact subassembly 26.
A push rod subassembly 74 is provided that includes a push rod
carrier 76 and a push rod 78. The push rod carrier 76 cooperates
with other applicator components to ensure that the sensor is
properly inserted into the host's skin, namely the push rod carrier
76 carries the push rod 78 between its extended and retracted
positions. In this embodiment, the push rod 78 is configured to
slidably nest within the needle 72, which allows for the sensor 32
to be pushed (released) from the needle 72 upon retraction of the
needle, which is described in more detail with reference to FIGS.
7A through 7D. In some embodiments, a slight bend or serpentine
shape is designed into or allowed in the sensor in order to
maintain the sensor within the needle by interference. While not
wishing to be bound by theory, it is believed that a slight
friction fit of the sensor within the needle minimizes motion of
the sensor during withdrawal of the needle and maintains the sensor
within the needle prior to withdrawal of the needle.
A plunger subassembly 22 is provided that includes a plunger 80 and
plunger cap 82. The plunger subassembly 22 cooperates with other
applicators components to ensure proper insertion and subsequent
retraction of the applicator components. In this embodiment, the
plunger 80 is configured to engage with the push rod to ensure the
sensor remains extended (namely, in the host) during retraction,
such as is described in more detail with reference to FIG. 7C.
Sensor Insertion
FIGS. 7A through 7D are schematic side cross-sectional views that
illustrate the applicator components and their cooperating
relationships at various stages of sensor insertion. FIG. 7A
illustrates the needle and sensor loaded prior to sensor insertion.
FIG. 7B illustrates the needle and sensor after sensor insertion.
FIG. 7C illustrates the sensor and needle during needle retraction.
FIG. 7D illustrates the sensor remaining within the contact
subassembly after needle retraction. Although the embodiments
described herein suggest manual insertion and/or retraction of the
various components, automation of one or more of the stages can
also be employed. For example, spring-loaded mechanisms that can be
triggered to automatically insert and/or retract the sensor,
needle, or other cooperative applicator components can be
implemented.
Referring to FIG. 7A, the sensor 32 is shown disposed within the
needle 72, which is disposed within the guide tube 66. In this
embodiment, the guide tube 66 is provided to maintain an opening
within the contact subassembly 26 and/or contacts 28 to provide
minimal friction between the needle 72 and the contact subassembly
26 and/or contacts 28 during insertion and retraction of the needle
72. However, the guide tube is an optional component, which can be
advantageous in some embodiments wherein the contact subassembly 26
and/or the contacts 28 are formed from an elastomer or other
material with a relatively high friction coefficient, and which can
be omitted in other embodiments wherein the contact subassembly 26
and or the contacts 28 are formed from a material with a relatively
low friction coefficient (for example, hard plastic or metal). A
guide tube, or the like, can be preferred in embodiments wherein
the contact subassembly 26 and/or the contacts 28 are formed from a
material designed to frictionally hold the sensor 32 (see FIG. 7D),
for example, by the relaxing characteristics of an elastomer, or
the like. In these embodiments, the guide tube is provided to ease
insertion of the needle through the contacts, while allowing for a
frictional hold of the contacts on the sensor 32 upon subsequent
needle retraction. Stabilization of the sensor in or on the
contacts 28 is described in more detail with reference to FIG. 7D
and following. Although FIG. 7A illustrates the needle and sensor
inserted into the contacts subassembly as the initial loaded
configuration, alternative embodiments contemplate a step of
loading the needle through the guide tube 66 and/or contacts 28
prior to sensor insertion.
Referring to FIG. 7B, the sensor 32 and needle 72 are shown in an
extended position. In this stage, the pushrod 78 has been forced to
a forward position, for example by pushing on the plunger shown in
FIG. 6, or the like. The plunger 22 (FIG. 6) is designed to
cooperate with other of the applicator components to ensure that
sensor 32 and the needle 72 extend together to a forward position
(as shown); namely, the push rod 78 is designed to cooperate with
other of the applicator components to ensure that the sensor 32
maintains the forward position simultaneously within the needle
72.
Referring to FIG. 7C, the needle 72 is shown during the retraction
process. In this stage, the push rod 78 is held in its extended
(forward) position in order to maintain the sensor 32 in its
extended (forward) position until the needle 72 has substantially
fully retracted from the contacts 28. Simultaneously, the
cooperating applicator components retract the needle 72 and guide
tube 66 backward by a pulling motion (manual or automated) thereon.
In preferred embodiments, the guide tube carrier 64 (FIG. 6)
engages with cooperating applicator components such that a backward
(retraction) motion applied to the guide tube carrier retracts the
needle 72 and guide tube 66, without (initially) retracting the
push rod 78. In an alternative embodiment, the push rod 78 can be
omitted and the sensor 32 held it its forward position by a cam,
elastomer, or the like, which is in contact with a portion of the
sensor while the needle moves over another portion of the sensor.
One or more slots can be cut in the needle to maintain contact with
the sensor during needle retraction.
Referring to FIG. 7D, the needle 72, guide tube 66, and push rod 78
are all retracted from contact subassembly 26, leaving the sensor
32 disposed therein. The cooperating applicator components are
designed such that when the needle 72 has substantially cleared
from the contacts 28 and/or contact subassembly 26, the push rod 78
is retracted along with the needle 72 and guide tube 66. The
applicator 12 can then be released (manually or automatically) from
the contacts 28, such as is described in more detail elsewhere
herein, for example with reference to FIGS. 8D and 9A.
The preferred embodiments are generally designed with elastomeric
contacts to ensure a retention force that retains the sensor 32
within the mounting unit 14 and to ensure stable electrical
connection of the sensor 32 and its associated contacts 28.
Although the illustrated embodiments and associated text describe
the sensor 32 extending through the contacts 28 to form a friction
fit therein, a variety of alternatives are contemplated. In one
alternative embodiment, the sensor is configured to be disposed
adjacent to the contacts (rather than between the contacts). The
contacts can be constructed in a variety of known configurations,
for example, metallic contacts, cantilevered fingers, pogo pins, or
the like, which are configured to press against the sensor after
needle retraction.
The illustrated embodiments are designed with coaxial contacts 28;
namely, the contacts 28 are configured to contact the working and
reference electrodes 44, 46 axially along the distal portion 42 of
the sensor 32 (see FIG. 5A). As shown in FIG. 5A, the working
electrode 44 extends farther than the reference electrode 46, which
allows coaxial connection of the electrodes 44, 46 with the
contacts 28 at locations spaced along the distal portion of the
sensor (see also FIGS. 9B and 10B). Although the illustrated
embodiments employ a coaxial design, other designs are contemplated
within the scope of the preferred embodiments. For example, the
reference electrode can be positioned substantially adjacent to
(but spaced apart from) the working electrode at the distal portion
of the sensor. In this way, the contacts 28 can be designed
side-by-side rather than co-axially along the axis of the
sensor.
FIG. 8A is a perspective view of an applicator and mounting unit in
one embodiment including a safety latch mechanism 84. The safety
latch mechanism 84 is configured to lock the plunger subassembly 22
in a stationary position such that it cannot be accidentally pushed
prior to release of the safety latch mechanism. In this embodiment,
the sensor system 10 is preferably packaged (e.g., shipped) in this
locked configuration, wherein the safety latch mechanism 84 holds
the plunger subassembly 22 in its extended position, such that the
sensor 32 cannot be prematurely inserted (e.g., accidentally
released). The safety latch mechanism 84 is configured such that a
pulling force shown in the direction of the arrow (see FIG. 8A)
releases the lock of the safety latch mechanism on the plunger
subassembly, thereby allowing sensor insertion. Although one safety
latch mechanism that locks the plunger subassembly is illustrated
and described herein, a variety of safety latch mechanism
configurations that lock the sensor to prevent it from prematurely
releasing (i.e., that lock the sensor prior to release of the
safety latch mechanism) are contemplated, as can be appreciated by
one skilled in the art, and fall within the scope of the preferred
embodiments.
FIG. 8A additionally illustrates a force-locking mechanism 86
included in certain alternative embodiments of the sensor system,
wherein the force-locking mechanism 86 is configured to ensure a
proper mate between the electronics unit 16 and the mounting unit
14 (see FIG. 12A, for example). In embodiments wherein a seal is
formed between the mounting unit and the electronics unit, as
described in more detail elsewhere herein, an appropriate force may
be required to ensure a seal has sufficiently formed therebetween;
in some circumstances, it can be advantageous to ensure the
electronics unit has been properly mated (e.g., snap-fit or
sealingly mated) to the mounting unit. Accordingly, upon release of
the applicator 12 from the mounting unit 14 (after sensor
insertion), and after insertion of the electronics unit 16 into the
mounting unit 14, the force-locking mechanism 86 allows the user to
ensure a proper mate and/or seal therebetween. In practice, a user
pivots the force-locking mechanism such that it provides force on
the electronics unit 16 by pulling up on the circular tab
illustrated in FIG. 8A. Although one system and one method for
providing a secure and/or sealing fit between the electronics unit
and the mounting unit are illustrated, various other force-locking
mechanisms can be employed that utilize a variety of systems and
methods for providing a secure and/or sealing fit between the
electronics unit and the mounting unit (housing).
FIGS. 8B to 8D are side views of an applicator and mounting unit in
one embodiment, showing various stages of sensor insertion. FIG. 8B
is a side view of the applicator matingly engaged to the mounting
unit prior to sensor insertion. FIG. 8C is a side view of the
mounting unit and applicator after the plunger subassembly has been
pushed, extending the needle and sensor from the mounting unit
(namely, through the host's skin). FIG. 8D is a side view of the
mounting unit and applicator after the guide tube subassembly has
been retracted, retracting the needle back into the applicator.
Although the drawings and associated text illustrate and describe
embodiments wherein the applicator is designed for manual insertion
and/or retraction, automated insertion and/or retraction of the
sensor/needle, for example, using spring-loaded components, can
alternatively be employed.
The preferred embodiments advantageously provide a system and
method for easy insertion of the sensor and subsequent retraction
of the needle in a single push-pull motion. Because of the
mechanical latching system of the applicator, the user provides a
continuous force on the plunger cap 82 and guide tube carrier 64
that inserts and retracts the needle in a continuous motion. When a
user grips the applicator, his or her fingers grasp the guide tube
carrier 64 while his or her thumb (or another finger) is positioned
on the plunger cap 82. The user squeezes his or her fingers and
thumb together continuously, which causes the needle to insert (as
the plunger slides forward) and subsequently retract (as the guide
tube carrier slides backward) due to the system of latches located
within the applicator (FIGS. 6 to 8) without any necessary change
of grip or force, leaving the sensor implanted in the host. In some
embodiments, a continuous torque, when the applicator components
are configured to rotatingly engage one another, can replace the
continuous force. Some prior art sensors, in contrast to the
sensors of the preferred embodiments, suffer from complex,
multi-step, or multi-component insertion and retraction steps to
insert and remove the needle from the sensor system.
FIG. 8B shows the mounting unit and applicator in the ready
position. The sensor system can be shipped in this configuration,
or the user can be instructed to mate the applicator 12 with the
mounting unit 14 prior to sensor insertion. The insertion angle
.alpha. is preferably fixed by the mating engagement of the
applicator 12. In the illustrated embodiment, the insertion angle
.alpha. is fixed in the applicator 12 by the angle of the
applicator body base 60 with the shaft of the applicator body 18.
However, a variety of systems and methods of ensuring proper
placement can be implemented. Proper placement ensures that at
least a portion of the sensor 32 extends below the dermis of the
host upon insertion. In alternative embodiments, the sensor system
10 is designed with a variety of adjustable insertion angles. A
variety of insertion angles can be advantageous to accommodate a
variety of insertion locations and/or individual dermis
configurations (for example, thickness of the dermis). In preferred
embodiments, the insertion angle .alpha. is from about 0 to about
90 degrees, more preferably from about 30 to about 60 degrees, and
even more preferably about 45 degrees.
In practice, the mounting unit is placed at an appropriate location
on the host's skin, for example, the skin of the arm, thigh, or
abdomen. Thus, removing the backing layer 9 from the adhesive layer
8 and pressing the base portion of the mounting unit on the skin
adheres the mounting unit to the host's skin.
FIG. 8C shows the mounting unit and applicator after the needle 72
has been extended from the mounting unit 14 (namely, inserted into
the host) by pushing the push rod subassembly 22 into the
applicator 12. In this position, the sensor 32 is disposed within
the needle 72 (namely, in position within the host), and held by
the cooperating applicator components. In alternative embodiments,
the mounting unit and/or applicator can be configured with the
needle/sensor initially extended. In this way, the mechanical
design can be simplified and the plunger-assisted insertion step
can be eliminated or modified. The needle can be simply inserted by
a manual force to puncture the host's skin, and only one (pulling)
step is required on the applicator, which removes the needle from
the host's skin.
FIG. 8D shows the mounting unit and applicator after the needle 72
has been retracted into the applicator 12, exposing the sensor 32
to the host's tissue. During needle retraction, the push rod
subassembly maintains the sensor in its extended position (namely,
within the host). In preferred embodiments, retraction of the
needle irreversibly locks the needle within the applicator so that
it cannot be accidentally and/or intentionally released,
reinserted, or reused. The applicator is preferably configured as a
disposable device to reduce or eliminate a possibility of exposure
of the needle after insertion into the host. However a reusable or
reloadable applicator is also contemplated in some alternative
embodiments. After needle retraction, the applicator 12 can be
released from the mounting unit, for example, by pressing the
release latch(es) 30, and the applicator disposed of appropriately.
In alternative embodiments, other mating and release configurations
can be implemented between the mounting unit and the applicator, or
the applicator can automatically release from the mounting unit
after sensor insertion and subsequent needle retraction. In one
alternative embodiment, a retention hold (e.g., ball and detent
configuration) holds and releases the electronics unit (or
applicator).
FIG. 8J is a perspective view of a sensor system 10 showing the
electronics unit 16 releasably attached to the housing 24 and a
safety latch mechanism 84 in one embodiment. FIG. 8K is a
perspective view of the sensor system 10 of FIG. 8J showing the
electronics unit 16 releasably attached to the housing 24 and the
safety latch mechanism 84 engaging the electronics unit/housing
subassembly.
In some embodiments, a tool is provided with the system, which is
configured and arranged to assist a user in releasing the
electronics unit from the housing. In one exemplary embodiment such
as illustrated herein, the tool is integral with the safety latch
mechanism 84. In some embodiments, the housing 24 includes release
tabs 30, configured and arranged to assist the user in releasing
the electronics unit 16 from the housing 24; for example, the
release tabs 30 are configured such that outward pressure on the
tabs releases the electronics unit 16 from the housing 24 (however
they can be configured for inward pressure as well). Although the
tabs can be manually pulled (or pushed), for example by a user's
fingers, the safety latch mechanism is configured and arranged with
protrusions 324 sized to fit around the electronics unit, such that
downward pressure on the tool (e.g., safety latch mechanism 84)
applies outward pressure on the tabs 30 of the housing 24, thereby
releasing the electronics unit 16 there from (see FIG. 8K).
In one alternative embodiment, the mounting unit is configured to
releasably mate with the applicator and electronics unit in a
manner such that when the applicator is releasably mated to the
mounting unit (e.g., after sensor insertion), the electronics unit
is configured to slide into the mounting unit, thereby triggering
release of the applicator and simultaneous mating of the
electronics unit to the mounting unit. Cooperating mechanical
components, for example, sliding ball and detent type
configurations, can be used to accomplish the simultaneous mating
of electronics unit and release of the applicator.
FIGS. 8E to 8G are perspective views of a sensor system 310 of an
alternative embodiment, including an applicator 312, electronics
unit 316, and mounting unit 314, showing various stages of
applicator release and/or electronic unit mating. FIG. 8E is a
perspective view of the applicator matingly engaged to the mounting
unit after sensor insertion. FIG. 8F is a perspective view of the
mounting unit and applicator matingly engaged while the electronics
unit is slidingly inserted into the mounting unit. FIG. 8G is a
perspective view of the electronics unit matingly engaged with the
mounting unit after the applicator has been released.
In general, the sensor system 310 comprises a sensor adapted for
transcutaneous insertion into a host's skin; a housing 314 adapted
for placement adjacent to the host's skin; an electronics unit 316
releasably attachable to the housing; and an applicator 312
configured to insert the sensor through the housing 314 and into
the skin of the host, wherein the applicator 312 is adapted to
releasably mate with the housing 314, and wherein the system 310 is
configured to release the applicator 312 from the housing when the
electronics unit 316 is attached to the housing 314.
FIG. 8E shows the sensor system 310 after the sensor has been
inserted and prior to release of the applicator 312. In this
embodiment, the electronics unit 316 is designed to slide into the
mounting unit 314. Preferably, the electronics unit 316 is
configured and arranged to slide into the mounting unit 314 in only
one orientation. In the illustrated embodiment, the insertion end
is slightly tapered and dovetailed in order to guide insertion of
the electronics unit 316 into the housing 314; however other
self-alignment configurations are possible. In this way, the
electronics unit 316 self-aligns and orients the electronics unit
316 in the housing, ensuring a proper fit and a secure electronic
connection with the sensor.
FIG. 8F shows the sensor system 310 after the electronics unit 316
has been inserted therein. Preferably, the electronic unit 316
slide-fits into the mounting unit. In some embodiments, the sensor
system 310 can be designed to allow the electronics unit 316 to be
attached to the mounting unit 314 (i.e., operably connected to the
sensor) before the sensor system 310 is affixed to the host.
Advantageously, this design provides mechanical stability for the
sensor during transmitter insertion.
FIG. 8G shows the sensor system 310 upon release of the applicator
312 from the mounting unit 314 and electronics unit 316. In this
embodiment, the sensor system 310 is configured such that mating
the electronics unit to the mounting unit triggers the release of
the applicator 312 from the mounting unit 314.
Thus, the above described sensor system 310, also referred to as
the slide-in system, allows for self-alignment of the electronics
unit, creates an improved seal around the contacts due to greater
holding force, provides mechanical stability for the sensor during
insertion of the electronics unit, and causes automatic release of
the applicator and simultaneous lock of the electronics unit into
the mounting unit.
Although the overall design of the sensor system 10 results in a
miniaturized volume as compared to numerous conventional devices,
as described in more detail below; the sensor system 310 further
enables a reduction in volume, as compared to, for example, the
sensor system 10 described above.
FIGS. 8H and 8I are comparative top views of the sensor system
shown in the alternative embodiment illustrated in FIGS. 8E to 8G
and compared to the embodiments illustrated elsewhere (see FIGS. 1
to 3 and 10 to 12, for example). Namely, the alternative embodiment
described with reference to FIGS. 8E to 8G further enables reduced
size (e.g., mass, volume, and the like) of the device as compared
to certain other devices. It has been discovered that the size
(including volume and/or surface area) of the device can affect the
function of the device. For example, motion of the mounting
unit/electronics unit caused by external influences (e.g., bumping
or other movement on the skin) is translated to the sensor in vivo,
causing motion artifact (e.g., an effect on the signal, or the
like). Accordingly, by enabling a reduction of size, a more stable
signal with overall improved patient comfort can be achieved.
Accordingly, slide-in system 310 described herein, including the
systems and methods for inserting the sensor and connecting the
electronics unit to the mounting unit, enables the mounting unit
316/electronics unit 314 subassembly to be designed with a volume
of less than about 10 cm.sup.3, more preferably less than about 8
cm.sup.3, and even more preferably less than about 6 cm.sup.3, 5
cm.sup.3, or 4 cm.sup.3 or less. In general, the mounting unit
316/electronics unit 314 subassembly comprises a first major
surface and a second major surface opposite the first major
surface. The first and second major surfaces together preferably
account for at least about 50% of the surface area of the device;
the first and second major surfaces each define a surface area,
wherein the surface area of each major surface is less than or
equal to about 10 cm.sup.2, preferably less than or equal to about
8 cm.sup.2, and more preferably less than or equal to about 6.5
cm.sup.2, 6 cm.sup.2, 5.5 cm.sup.2, 5 cm.sup.2, 4.5 cm.sup.2, or 4
cm.sup.2 or less. Typically, the mounting unit 316/electronics unit
314 subassembly has a length 320 of less than about 40 mm by a
width 322 of less than about 20 mm and a thickness of less than
about 10 mm, and more preferably a length 320 less than or equal to
about 35 mm by a width 322 less than or equal to about 18 mm by a
thickness of less than or equal to about 9 mm.
In some embodiments, the sensor 32 exits the base of the mounting
unit 14 at a location distant from an edge of the base. In some
embodiments, the sensor 32 exits the base of the mounting unit 14
at a location substantially closer to the center than the edges
thereof. While not wishing to be bound by theory, it is believed
that by providing an exit port for the sensor 32 located away from
the edges, the sensor 32 can be protected from motion between the
body and the mounting unit, snagging of the sensor by an external
source, and/or environmental contaminants (e.g., microorganisms)
that can migrate under the edges of the mounting unit. In some
embodiments, the sensor exits the mounting unit away from an outer
edge of the device. FIG. 21 shows transcutaneous glucose sensor
data and corresponding blood glucose values obtained over
approximately seven days in a human, wherein the transcutaneous
glucose sensor data was configured with an exit port situated at a
location substantially closer to the center than the edges of the
base.
In some alternative embodiments, however, the sensor exits the
mounting unit 14 at an edge or near an edge of the device. In some
embodiments, the mounting unit is configured such that the exit
port (location) of the sensor is adjustable; thus, in embodiments
wherein the depth of the sensor insertion is adjustable,
six-degrees of freedom can thereby be provided.
Extensible Adhesive Layer
In certain embodiments, an adhesive layer is used with the sensor
system. A variety of design parameters are desirable when choosing
an adhesive layer for the mounting unit. For example: 1) the
adhesive layer can be strong enough to maintain full contact at all
times and during all movements (devices that release even slightly
from the skin have a greater risk of contamination and infection),
2) the adhesive layer can be waterproof or water permeable such
that the host can wear the device even while heavily perspiring,
showering, or even swimming in some cases, 3) the adhesive layer
can be flexible enough to withstand linear and rotational forces
due to host movements, 4) the adhesive layer can be comfortable for
the host, 5) the adhesive layer can be easily releasable to
minimize host pain, 6) and/or the adhesive layer can be easily
releasable so as to protect the sensor during release.
Unfortunately, these design parameters are difficult to
simultaneously satisfy using known adhesive layers, for example,
strong medical adhesive layers are available but are usually
non-precise (for example, requiring significant "ripping" force
during release) and can be painful during release due to the
strength of their adhesion.
Therefore, the preferred embodiments provide an adhesive layer 8'
for mounting the mounting unit onto the host, including a
sufficiently strong medical adhesive layer that satisfies one or
more strength and flexibility requirements described above, and
further provides a for easy, precise and pain-free release from the
host's skin. FIG. 9A is a side view of the sensor assembly,
illustrating the sensor implanted into the host with mounting unit
adhered to the host's skin via an adhesive layer in one embodiment.
Namely, the adhesive layer 8' is formed from an extensible material
that can be removed easily from the host's skin by stretching it
lengthwise in a direction substantially parallel to (or up to about
35 degrees from) the plane of the skin. It is believed that this
easy, precise, and painless removal is a function of both the high
extensibility and easy stretchability of the adhesive layer.
In one embodiment, the extensible adhesive layer includes a
polymeric foam layer or is formed from adhesive layer foam. It is
believed that the conformability and resiliency of foam aids in
conformation to the skin and flexibility during movement of the
skin. In another embodiment, a stretchable solid adhesive layer,
such as a rubber-based or an acrylate-based solid adhesive layer
can be used. In another embodiment, the adhesive layer comprises a
film, which can aid in increasing load bearing strength and rupture
strength of the adhesive layer
FIGS. 9B to 9C illustrate initial and continued release of the
mounting unit from the host's skin by stretching the extensible
adhesive layer in one embodiment. To release the device, the
backing adhesive layer is pulled in a direction substantially
parallel to (or up to about 35 degrees from) the plane of the
device. Simultaneously, the extensible adhesive layer stretches and
releases from the skin in a relatively easy and painless
manner.
In one implementation, the mounting unit is bonded to the host's
skin via a single layer of extensible adhesive layer 8', which is
illustrated in FIGS. 9A to 9C. The extensible adhesive layer
includes a substantially non-extensible pull-tab 52, which can
include a light adhesive layer that allows it to be held on the
mounting unit 14 prior to release. Additionally, the adhesive layer
can further include a substantially non-extensible holding tab 54,
which remains attached to the mounting unit during release
stretching to discourage complete and/or uncontrolled release of
the mounting unit from the skin.
In one alternative implementation, the adhesive layer 8' includes
two-sides, including the extensible adhesive layer and a backing
adhesive layer (not shown). In this embodiment, the backing
adhesive layer is bonded to the mounting unit's back surface 25
while the extensible adhesive layer 8' is bonded to the host's
skin. Both adhesive layers provide sufficient strength,
flexibility, and waterproof or water permeable characteristics
appropriate for their respective surface adhesion. In some
embodiments, the backing and extensible adhesive layers are
particularly designed with an optimized bond for their respective
bonding surfaces (namely, the mounting unit and the skin).
In another alternative implementation, the adhesive layer 8'
includes a double-sided extensible adhesive layer surrounding a
middle layer or backing layer (not shown). The backing layer can
comprise a conventional backing film or can be formed from foam to
enhance comfort, conformability, and flexibility. Preferably, each
side of the double-sided adhesive layer is respectively designed
for appropriate bonding surface (namely, the mounting unit and
skin). A variety of alternative stretch-release configurations are
possible. Controlled release of one or both sides of the adhesive
layer can be facilitated by the relative lengths of each adhesive
layer side, by incorporation of a non-adhesive layer zone, or the
like.
FIGS. 10A and 10B are perspective and side cross-sectional views,
respectively, of the mounting unit immediately following sensor
insertion and release of the applicator from the mounting unit. In
one embodiment, such as illustrated in FIGS. 10A and 10B, the
contact subassembly 26 is held in its insertion position,
substantially at the insertion angle .alpha. of the sensor.
Maintaining the contact subassembly 26 at the insertion angle
.alpha. during insertion enables the sensor 32 to be easily
inserted straight through the contact subassembly 26. The contact
subassembly 26 further includes a hinge 38 that allows movement of
the contact subassembly 26 from an angled to a flat position. The
term "hinge," as used herein, is a broad term and is used in its
ordinary sense, including, without limitation, a mechanism that
allows articulation of two or more parts or portions of a device.
The term is broad enough to include a sliding hinge, for example, a
ball and detent type hinging mechanism.
Although the illustrated embodiments describe a fixed insertion
angle designed into the applicator, alternative embodiments can
design the insertion angle into other components of the system. For
example, the insertion angle can be designed into the attachment of
the applicator with the mounting unit, or the like. In some
alternative embodiments, a variety of adjustable insertion angles
can be designed into the system to provide for a variety of host
dermis configurations.
FIG. 10B illustrates the sensor 32 extending from the mounting unit
14 by a preselected distance, which defines the depth of insertion
of the sensor into the host. The dermal and subcutaneous make-up of
animals and humans is variable and a fixed depth of insertion may
not be appropriate for all implantations. Accordingly, in an
alternative embodiment, the distance that the sensor extends from
the mounting unit is adjustable to accommodate a variety of host
body-types. For example, the applicator 12 can be designed with a
variety of adjustable settings, which control the distance that the
needle 72 (and therefore the sensor 32) extends upon sensor
insertion. One skilled in the art appreciates a variety of means
and mechanisms can be employed to accommodate adjustable sensor
insertion depths, which are considered within the scope of the
preferred embodiments. The preferred insertion depth is from about
0.1 mm or less to about 2 cm or more, preferably from about 0.15,
0.2, 0.25, 0.3, 0.35, 0.4, or 0.45 mm to about 0.5, 0.6, 0.7, 0.8,
0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, or 1.9 cm.
FIGS. 11A and 11B are perspective and side cross-sectional views,
respectively, of the mounting unit after articulating the contact
subassembly to its functional position (which is also referred to
as an inserted, implanted, or sensing position). The hinge 38
enables the contact subassembly 26 to tilt from its insertion
position (FIG. 10) to its functional position (FIG. 11) by pressing
downward on the contact subassembly, for example. Certain
embodiments provide this pivotal movement via two separate pieces
(the contact subassembly 26 and the mounting unit 14 connected by a
hinge, for example, a mechanical or adhesive layer joint or hinge.
A variety of pivoting, articulating, and/or hinging mechanisms can
be employed with the sensors of preferred embodiments. For example,
the hinge can be formed as a part of the contact subassembly 26.
The contact subassembly can be formed from a flexible piece of
material (such as silicone, urethane rubber, or other flexible or
elastomeric material), wherein the material is sufficiently
flexible to enable bending or hinging of the contact subassembly
from an angle appropriate for insertion (FIGS. 10A and 10B) to a
lower functional configuration (FIGS. 11A and 11B).
The relative pivotal movement of the contact subassembly is
advantageous, for example, for enabling the design of a low profile
device while providing support for an appropriate needle insertion
angle. In its insertion position, the sensor system is designed for
easy sensor insertion while forming a stable electrical connection
with the associated contacts 28. In its functional position, the
sensor system maintains a low profile for convenience, comfort, and
discreetness during use. Thus, the sensor systems of preferred
embodiments are advantageously designed with a hinging
configuration to provide an optimum guided insertion angle while
maintaining a low profile device during sensor use.
In some embodiments, a shock-absorbing member or feature is
incorporated into the design of the sensor and configured to absorb
movement of the in vivo and/or ex vivo portion of the sensor.
Conventional analyte sensors can suffer from motion-related
artifact associated with host movement when the host is using the
device. For example, when a transcutaneous analyte sensor is
inserted into the host, various movements on the sensor (for
example, relative movement between the in vivo portion and the ex
vivo portion and/or movement within the host) create stresses on
the device and can produce noise in the sensor signal. Accordingly
in some embodiments, a shock-absorbing member is located on the
sensor/mounting unit in a location that absorbs stresses associated
with the above-described movement.
In the preferred embodiments, the sensor 32 bends from a
substantially straight to substantially bent configuration upon
pivoting of the contact subassembly from the insertion to
functional position. The substantially straight sensor
configuration during insertion advantageously provides ease of
sensor insertion, while the substantial bend in the sensor in its
functional position advantageously provides stability on the
proximal end of the sensor with flexibility/mobility on the distal
end of the sensor. Additionally, motion within the mounting unit
(e.g., caused by external forces to the mounting unit, movement of
the skin, and the like) does not substantially translate to the in
vivo portion of the sensor. Namely, the bend formed within the
sensor 32 functions to break column strength, causing flexion that
effectively absorbs movements on the sensor during use.
Additionally, the sensor can be designed with a length such that
when the contact subassembly 26 is pivoted to its functional
position (FIG. 10B), the sensor pushes forward and flexes, allowing
it to absorb motion between the in vivo and ex vivo portions of the
sensor. It is believed that both of the above advantages minimize
motion artifact on the sensor signal and/or minimize damage to the
sensor caused by movement, both of which (motion artifact and
damage) have been observed in conventional transcutaneous
sensors.
In some alternative embodiments, the shock-absorbing member can be
an expanding and contracting member, such as a spring, accordion,
telescoping, or bellows-type device. In general, the shock
absorbing member can be located such that relative movement between
the sensor, the mounting unit, and the host is absorbed without (or
minimally) affecting the connection of the sensor to the mounting
unit and/or the sensor stability within the implantation site; for
example, the shock-absorbing member can be formed as a part of or
connected to the sensor 32.
FIGS. 12A to 12C are perspective and side views of a sensor system
including the mounting unit 14 and electronics unit 16 attached
thereto. After sensor insertion, the transcutaneous analyte sensor
system 10 measures a concentration of an analyte or a substance
indicative of the concentration or presence of the analyte as
described above. Although the examples are directed to a glucose
sensor, the analyte sensor can be a sensor capable of determining
the level of any suitable analyte in the body, for example, oxygen,
lactase, insulin, hormones, cholesterol, medicaments, viruses, or
the like. Once the electronics unit 16 is connected to the mounting
unit 14, the sensor 32 is able to measure levels of the analyte in
the host.
Detachable connection between the mounting unit 14 and electronics
unit 16 provides improved manufacturability, namely, the relatively
inexpensive mounting unit 14 can be disposed of when replacing the
sensor system after its usable life, while the relatively more
expensive electronics unit 16 can be reusable with multiple sensor
systems. In certain embodiments, the electronics unit 16 is
configured with programming, for example, initialization,
calibration reset, failure testing, or the like, each time it is
initially inserted into the cavity and/or each time it initially
communicates with the sensor 32. However, an integral
(non-detachable) electronics unit can be configured as is
appreciated by one skilled in the art.
Referring to the mechanical fit between the mounting unit 14 and
the electronics unit 16 (and/or applicator 12), a variety of
mechanical joints are contemplated, for example, snap fit,
interference fit, or slide fit. In the illustrated embodiment of
FIGS. 12A to 12C, tabs 120 are provided on the mounting unit 14
and/or electronics unit 16 that enable a secure connection
therebetween. The tabs 120 of the illustrated embodiment can
improve ease of mechanical connection by providing alignment of the
mounting unit and electronics unit and additional rigid support for
force and counter force by the user (e.g., fingers) during
connection. However, other configurations with or without guiding
tabs are contemplated, such as illustrated in FIGS. 10 and 11, for
example.
In some embodiments, wherein the housing (mounting unit) comprises
a flexible material, the electronics unit and housing are
configured and arranged such that the electronics unit is released
from the housing by a flexion of the housing. For example, the
system is configured such that when a user applies pressure to
opposing sides of the mounting unit, the electronics unit releases
there from. While not wishing to be bound by theory, it is believed
that such a design enhances the usability and therefore patient
acceptability of the system.
In some embodiments, the housing (mounting unit) and electronics
unit are configured such that the housing physically breaks upon
release of the electronics unit there from. This embodiment can be
particularly advantageous, for example, when the housing (mounting
unit) is configured for use with only one sensor and the
electronics unit is configured for reuse with more than one sensor.
Accordingly, the physical break of the sensor housing ensures
patient compliance with the single-use device (i.e., does not allow
reuse of the sensor). In one exemplary embodiment, the housing is
made from a material that is sufficiently brittle such that when a
user applies pressure to opposing sides of the housing, the
material that forms the housing is configured to physically fail
due to the forces applied by the user's hands. Suitable materials
for the housing of this embodiment include, for example,
polycarbonate, PLLA, ABS, PVC, and the like.
In some circumstances, a drift of the sensor signal can cause
inaccuracies in sensor performance and/or require re-calibration of
the sensor. Accordingly, it can be advantageous to provide a
sealant, whereby moisture (e.g., water and water vapor) cannot
substantially penetrate to the sensor and its connection to the
electrical contacts. The sealant described herein can be used alone
or in combination with the sealing member 36 described in more
detail above, to seal the sensor from moisture in the external
environment.
Preferably, the sealant fills in holes, crevices, or other void
spaces between the mounting unit 14 and electronics unit 16 and/or
around the sensor 32 within the mounting unit 32. For example, the
sealant can surround the sensor in the portion of the sensor 32
that extends through the contacts 28. Additionally, the sealant can
be disposed within the additional void spaces, for example a hole
122 that extends through the sealing member 36.
Preferably, the sealant comprises a water impermeable material or
compound, for example, oil, grease, or gel. In one exemplary
embodiment, the sealant comprises petroleum jelly and is used to
provide a moisture barrier surrounding the sensor 32. In one
experiment, petroleum jelly was liquefied by heating, after which a
sensor 32 was immersed into the liquefied petroleum jelly to coat
the outer surfaces thereof. The sensor was then assembled into a
housing and inserted into a host, during which deployment the
sensor was inserted through the electrical contacts 28 and the
petroleum jelly conforming therebetween. Sensors incorporating
petroleum jelly, such as described above, when compared to sensors
without the petroleum jelly moisture barrier exhibited less or no
signal drift over time when studied in a humid or submersed
environment. While not wishing to be bound by theory, it is
believed that incorporation of a moisture barrier surrounding the
sensor, especially between the sensor and its associated electrical
contacts, reduces or eliminates the effects of humidity on the
sensor signal. The viscosity of grease or oil-based moisture
barriers allows penetration into and through even small cracks or
crevices within the sensor and mounting unit, displacing moisture
and thereby increasing the sealing properties thereof. U.S. Pat.
Nos. 4,259,540 and 5,285,513 disclose materials suitable for use as
a water impermeable material (sealant).
Referring to the electrical fit between the sensor 32 and the
electronics unit 16, electrical contacts 28 (through which the
sensor extends) are configured to electrically connect with
mutually engaging contacts on the electronics unit 16. A variety of
configurations are contemplated; however, the mutually engaging
contacts operatively connect upon detachable connection of the
electronics unit 16 with the mounting unit 14, and are
substantially sealed from external moisture by sealing member 36.
Even with the sealing member, some circumstances may exist wherein
moisture can penetrate into the area surrounding the sensor 32 and
or contacts, for example, exposure to a humid or wet environment
(e.g., caused by sweat, showering, or other environmental causes).
It has been observed that exposure of the sensor to moisture can be
a cause of baseline signal drift of the sensor over time. For
example in a glucose sensor, the baseline is the component of a
glucose sensor signal that is not related to glucose (the amount of
signal if no glucose is present), which is ideally constant over
time. However, some circumstances my exist wherein the baseline can
fluctuate over time, also referred to as drift, which can be
caused, for example, by changes in a host's metabolism, cellular
migration surrounding the sensor, interfering species, humidity in
the environment, and the like.
In some embodiments, the mounting unit is designed to provide
ventilation (e.g., a vent hole 124) between the exit-site and the
sensor. In certain embodiments, a filter (not shown) is provided in
the vent hole 124 that allows the passage of air, while preventing
contaminants from entering the vent hole 124 from the external
environment. While not wishing to be bound by theory, it is
believed that ventilation to the exit-site (or to the sensor 32)
can reduce or eliminate trapped moisture or bacteria, which can
otherwise increase the growth and/or lifetime of bacteria adjacent
to the sensor.
In some alternative embodiments, a sealing material is provided,
which seals the needle and/or sensor from contamination of the
external environment during and after sensor insertion. For
example, one problem encountered in conventional transcutaneous
devices is infection of the exit-site of the wound. For example,
bacteria or contaminants can migrate from ex vivo, for example, any
ex vivo portion of the device or the ex vivo environment, through
the exit-site of the needle/sensor, and into the subcutaneous
tissue, causing contamination and infection. Bacteria and/or
contaminants can originate from handling of the device, exposed
skin areas, and/or leakage from the mounting unit (external to) on
the host. In many conventional transcutaneous devices, there exists
some path of migration for bacteria and contaminants to the
exit-site, which can become contaminated during sensor insertion or
subsequent handling or use of the device. Furthermore, in some
embodiments of a transcutaneous analyte sensor, the
insertion-aiding device (for example, needle) is an integral part
of the mounting unit; namely, the device stores the insertion
device after insertion of the sensor, which is isolated from the
exit-site (namely, point-of-entry of the sensor) after
insertion.
Accordingly, these alternative embodiments provide a sealing
material on the mounting unit, interposed between the housing and
the skin, wherein the needle and/or sensor are adapted to extend
through, and be sealed by, the sealing material. The sealing
material is preferably formed from a flexible material that
substantially seals around the needle/sensor. Appropriate flexible
materials include malleable materials, elastomers, gels, greases,
or the like (e.g., see U.S. Pat. Nos. 4,259,540 and 5,285,513).
However, not all embodiments include a sealing material, and in
some embodiments a clearance hole or other space surrounding the
needle and/or sensor is preferred.
In one embodiment, the base 24 of the mounting unit 14 is formed
from a flexible material, for example silicone, which by its
elastomeric properties seals the needle and/or sensor at the exit
port 126, such as is illustrated in FIGS. 11A and 11B. Thus,
sealing material can be formed as a unitary or integral piece with
the back surface 25 of the mounting unit 14, or with an adhesive
layer 8 on the back surface of the mounting unit, however
alternatively can be a separate part secured to the device. In some
embodiments, the sealing material can extend through the exit port
126 above or below the plane of the adhesive layer surface, or the
exit port 126 can comprise a septum seal such as those used in the
medical storage and disposal industries (for example, silica gel
sandwiched between upper and lower seal layers, such as layers
comprising chemically inert materials such as PTFE). A variety of
known septum seals can be implemented into the exit port of the
preferred embodiments described herein. Whether the sealing
material is integral with or a separate part attached to the
mounting unit 14, the exit port 126 is advantageously sealed so as
to reduce or eliminate the migration of bacteria or other
contaminants to or from the exit-site of the wound and/or within
the mounting unit.
During use, a host or caretaker positions the mounting unit at the
appropriate location on or near the host's skin and prepares for
sensor insertion. During insertion, the needle aids in sensor
insertion, after which the needle is retracted into the mounting
unit leaving the sensor in the subcutaneous tissue. In this
embodiment, the exit-port 126 includes a layer of sealing material,
such as a silicone membrane, that encloses the exit-port in a
configuration that protects the exit-site from contamination that
can migrate from the mounting unit or spacing external to the
exit-site. Thus, when the sensor 32 and/or needle 72 extend
through, for example, an aperture or a puncture in the sealing
material, to provide communication between the mounting unit and
subcutaneous space, a seal is formed therebetween. Elastomeric
sealing materials can be advantageous in some embodiments because
the elasticity provides a conforming seal between the needle/sensor
and the mounting unit and/or because the elasticity provides
shock-absorbing qualities allowing relative movement between the
device and the various layers of the host's tissue, for
example.
In some alternative embodiments, the sealing material includes a
bioactive agent incorporated therein. Suitable bioactive agents
include those which are known to discourage or prevent bacteria and
infection, for example, anti-inflammatory, antimicrobials,
antibiotics, or the like. It is believed that diffusion or presence
of a bioactive agent can aid in prevention or elimination of
bacteria adjacent to the exit-site.
In practice, after the sensor 32 has been inserted into the host's
tissue, and an electrical connection formed by mating the
electronics unit 16 to the mounting unit 14, the sensor measures an
analyte concentration continuously or continually, for example, at
an interval of from about fractions of a second to about 10 minutes
or more.
Sensor Electronics
The following description of sensor electronics associated with the
electronics unit is applicable to a variety of continuous analyte
sensors, such as non-invasive, minimally invasive, and/or invasive
(e.g., transcutaneous and wholly implantable) sensors. For example,
the sensor electronics and data processing as well as the receiver
electronics and data processing described below can be incorporated
into the wholly implantable glucose sensor disclosed in U.S. Patent
Publication No. US-2005-0245799-A1 and U.S. Patent Publication No.
US-2006-0015020-A1.
FIG. 13 is a block diagram that illustrates the electronics 132,
also referred to as sensor electronics and/or an electronics
module, associated with the sensor system 10 in one embodiment. In
this embodiment, a potentiostat 134 is shown, which is operably
connected to an electrode system (such as described above) and
provides a voltage to the electrodes, which biases the sensor to
enable measurement of an current signal indicative of the analyte
concentration in the host (also referred to as the analog portion).
In some embodiments, the potentiostat includes a resistor (not
shown) that translates the current into voltage. In some
alternative embodiments, a current to frequency converter is
provided that is configured to continuously integrate the measured
current, for example, using a charge counting device.
An A/D converter 136 digitizes the analog signal into a digital
signal, also referred to as "counts" for processing. Accordingly,
the resulting raw data stream in counts, also referred to as raw
sensor data, is directly related to the current measured by the
potentiostat 134.
A processor module 138 includes the central control unit that
controls the processing of the sensor electronics 132. In some
embodiments, the processor module includes a microprocessor,
however a computer system other than a microprocessor can be used
to process data as described herein, for example an ASIC can be
used for some or all of the sensor's central processing. The
processor typically provides semi-permanent storage of data, for
example, storing data such as sensor identifier (ID) and
programming to process data streams (for example, programming for
data smoothing and/or replacement of signal artifacts such as is
described in U.S. Patent Publication No. US-2005-0043598-A1). The
processor additionally can be used for the system's cache memory,
for example for temporarily storing recent sensor data. In some
embodiments, the processor module comprises memory storage
components such as ROM, RAM, dynamic-RAM, static-RAM, non-static
RAM, EEPROM, rewritable ROMs, flash memory, or the like.
In some embodiments, the processor module comprises a digital
filter, for example, an IIR or FIR filter, configured to smooth the
raw data stream from the A/D converter. Generally, digital filters
are programmed to filter data sampled at a predetermined time
interval (also referred to as a sample rate). In some embodiments,
wherein the potentiostat is configured to measure the analyte at
discrete time intervals, these time intervals determine the sample
rate of the digital filter. In some alternative embodiments,
wherein the potentiostat is configured to continuously measure the
analyte, for example, using a current-to-frequency converter as
described above, the processor module can be programmed to request
a digital value from the A/D converter at a predetermined time
interval, also referred to as the acquisition time. In these
alternative embodiments, the values obtained by the processor are
advantageously averaged over the acquisition time due the
continuity of the current measurement. Accordingly, the acquisition
time determines the sample rate of the digital filter. In preferred
embodiments, the processor module is configured with a programmable
acquisition time, namely, the predetermined time interval for
requesting the digital value from the A/D converter is programmable
by a user within the digital circuitry of the processor module. An
acquisition time of from about 2 seconds to about 512 seconds is
preferred; however any acquisition time can be programmed into the
processor module. A programmable acquisition time is advantageous
in optimizing noise filtration, time lag, and processing/battery
power.
Preferably, the processor module is configured to build the data
packet for transmission to an outside source, for example, an RF
transmission to a receiver as described in more detail below.
Generally, the data packet comprises a plurality of bits that can
include a sensor ID code, raw data, filtered data, and/or error
detection or correction. The processor module can be configured to
transmit any combination of raw and/or filtered data.
In some embodiments, the processor module further comprises a
transmitter portion that determines the transmission interval of
the sensor data to a receiver, or the like. In some embodiments,
the transmitter portion, which determines the interval of
transmission, is configured to be programmable. In one such
embodiment, a coefficient can be chosen (e.g., a number of from
about 1 to about 100, or more), wherein the coefficient is
multiplied by the acquisition time (or sampling rate), such as
described above, to define the transmission interval of the data
packet. Thus, in some embodiments, the transmission interval is
programmable between about 2 seconds and about 850 minutes, more
preferably between about 30 second and 5 minutes; however, any
transmission interval can be programmable or programmed into the
processor module. However, a variety of alternative systems and
methods for providing a programmable transmission interval can also
be employed. By providing a programmable transmission interval,
data transmission can be customized to meet a variety of design
criteria (e.g., reduced battery consumption, timeliness of
reporting sensor values, etc.)
Conventional glucose sensors measure current in the nanoAmp range.
In contrast to conventional glucose sensors, the preferred
embodiments are configured to measure the current flow in the
picoAmp range, and in some embodiments, femtoAmps. Namely, for
every unit (mg/dL) of glucose measured, at least one picoAmp of
current is measured. Preferably, the analog portion of the A/D
converter 136 is configured to continuously measure the current
flowing at the working electrode and to convert the current
measurement to digital values representative of the current. In one
embodiment, the current flow is measured by a charge counting
device (e.g., a capacitor). Thus, a signal is provided, whereby a
high sensitivity maximizes the signal received by a minimal amount
of measured hydrogen peroxide (e.g., minimal glucose requirements
without sacrificing accuracy even in low glucose ranges), reducing
the sensitivity to oxygen limitations in vivo (e.g., in
oxygen-dependent glucose sensors).
A power source, such as a battery 144, is operably connected to the
sensor electronics 132 and provides the power for at least one of
the sensor and the electronics unit. In one embodiment, the battery
is a lithium manganese dioxide battery; however, any appropriately
sized and powered battery can be used (for example, AAA,
nickel-cadmium, zinc-carbon, alkaline, lithium, nickel-metal
hydride, lithium-ion, zinc-air, zinc-mercury oxide, silver-zinc,
and/or hermetically-sealed). In some embodiments, the battery is
rechargeable, and/or a plurality of batteries can be used to power
the system. The sensor can be transcutaneously powered via an
inductive coupling, for example. In some embodiments, a quartz
crystal 96 is operably connected to the processor 138 and maintains
system time for the computer system as a whole, for example for the
programmable acquisition time within the processor module.
In some alternative embodiments, the power source includes a
flexible and/or thin battery. In some embodiments, the flexible
and/or thin battery is at least one of disposed in the adhesive
layer and laminated to the adhesive layer (and can be operatively
connected to the sensor and/or electronics unit); in one such
embodiment, the sensor (and associated adhesive layer) are
configured for single-use and the electronics unit is configured
for reuse with more than one sensor. By designing the battery into
the disposable portion of the sensor, the overall size of the
sensor system (e.g., housing and/or electronics unit) can be
reduced, particularly by the reduction of the size (e.g., aspect
ratio) of the battery. In some embodiments, the flexible battery is
designed with a thickness of from about 0.005, 0.010, 0.015, 0.020,
0.025, 0.030, 0.040, 0.050 inches or less to about 0.075, 0.080,
0.090, 0.100, 0.125 inches or more; while the length and width of
the battery can be as large as the overall length and width of the
sensor system or one of its components.
In one exemplary alternative embodiment, the flexible battery
includes a plurality of individual cells located one after the
other along at least a portion of a planar substrate (e.g.,
identical, evenly spaced cells), the individual cells are connected
in series and have respective anode and cathode electrodes for each
of the cells. In one alternative embodiment, the flexible battery
includes an anode layer and a cathode layer in superposed
relationship. U.S. Pat. No. 5,567,543 to Constable, which is
incorporated herein by reference in its entirety, describes
suitable flexible battery structures that can be incorporated into
the preferred embodiment.
In some alternative embodiments, the power source is located in or
on the housing (mounting unit); in one such embodiment, the sensor
(and associated housing) are configured for single-use and the
electronics unit is configured for reuse with more than one sensor.
By designing the battery into the disposable portion of the sensor,
the size of the sensor system (e.g., electronics unit) can be
reduced, shelf-life issues of a reusable battery can be eliminated,
and longevity of the battery can be reduced. In some embodiments,
the overall sensor system, including the housing and electronics
unit, is designed with a thickness of at least about 0.030 inches
greater than the thickness of the battery. In some embodiments, the
overall thickness is from about 0.040 inches or less to about 0.350
inches or more, preferably from about 0.0750 inches or less to
about 0.250 inches or more, and more preferably from about 0.100
inches or less to about 0.200 inches or more; while the length and
width of the battery can be as large as the overall length and
width of the sensor system or one of its components.
In some exemplary alternative embodiments, the power source
includes a rigid, semi-rigid or flexible battery shaped to conform
to the housing (e.g., mounting unit) and/or electronics unit to
reduce its use of real estate on the system and thereby decrease
the overall size of the sensor system, particularly the housing
and/or electronics unit. U.S. Pat. Nos. 5,572,401 and 3,023,259,
which are incorporated herein by reference in their entirety,
describe battery configurations suitable for shaping in a variety
of non-conventional manners, which can be incorporated into the
preferred embodiments.
In some embodiments, the system is configured and arranged such
that attachment of the electronics unit to the housing and/or
release of the electronics unit from the housing switches the power
source on and/or off respectively. In some embodiments, one or more
switches are operatively connected to the power source (e.g.,
battery), wherein a switch is configured to turn the power source
on when the electronics unit is attached to the housing and/or
wherein a switch is configured to turn the power source off when
the electronics unit is detached from the housing.
In some alternative embodiments, the system is configured to
reserve power on-board by maintaining an "off" or "power save"
state until the power is required for use. For example, the system
can be configured to maintain the minimal power requirement (which
can include no power) on-board until the electronics unit is
releasably attached to the housing and/or the sensor is inserted
and ready for use. In some embodiments, an electronics module
partially or fully housed within the electronics unit is provided,
wherein the electronics unit is attachable to and detachable from
the housing, and wherein the power source is configured to turn on
when the electronics unit is attached to the housing and/or turn
off when the electronics unit is detached from the housing. In some
embodiments, a proximity switch is provided and configured to
switch battery states when the housing and electronics are in
proximity to each other. In some embodiments, a movement (e.g.,
motion-activated) switch is provided and configured to switch
battery states (e.g., to or from a "sleep" state) when movement has
or has not been detected from some period of time. In some
embodiments, the housing and electronics unit have mutually
engaging contacts configured to switch the power on and/or off with
release and/or attachment of the electronics unit to the housing.
In another embodiment, wherein the housing and electronics unit are
integrally and/or attachedly provided for example, an insulating
tab can be provided to avoid contact of power source (e.g.,
battery) with the electrical contact points of the sensor system,
until the user is ready to insert the sensor, and is instructed to
"pull the tab," whereby the insulating tab is released and the
battery connects with and "switches on" the sensor system.
In some embodiments, a reed switch, such as a bi-stable magnetic
reed switch, in-line with one of the battery output terminals, is
provided and configured to turn the power source on when the
electronics unit is attached to the housing and/or off when the
electronics unit is detached from the housing. In some embodiments,
a bi-stable magnetic reed switch is a glass enclosed, magnetically
operated contact using reeds as the contacting members, wherein the
sealed glass body protects the contacts from external
contamination. Preferably, the switching device requires no power
to operate and its state can be latched and un-latched multiple
times. By its bi-stable nature, the magnetic reed switch will
retain its last state without the need for external power. Although
a few exemplary designs are discussed herein, a variety of switches
and/or designs can be implemented to control the battery output
voltage, as is appreciated by one skilled in the art. Accordingly,
the electronics unit can be manufactured and maintained in a
battery output disabled state (or power save state) until testing
or sensor insertion is required and the shelf life of the
electronics unit can be thereby extended.
In an alternative embodiment, the power source includes a
motion-driven power source, for example, a battery configured to be
charged and/or recharged kinetically. Thus, when a host wears the
sensor, the normal motion of the host will power and/or recharge
the battery.
In an alternative embodiment, the power source includes a glucose
consumption-driven power source, also referred to as
glucose-consuming device. The sensor system in this embodiment is
configured and arranged such that it integrates a dynamically
controlled load (e.g., glucose consuming device) that can run
directly from the energy generated by the oxidation of glucose on a
separate sacrificial membrane or from a battery integral to the
system. In some embodiments, the glucose-consuming device is
physically separate from the sensor system and runs as a slave
(e.g., via RF communication) of the sensor system (e.g., master),
or in an autonomous mode, whereby the device turns on when the
glucose level equivalent signal passes a predetermined threshold
value. Whether the glucose-consuming device is configured to run as
a slave or whether the glucose-consuming device is integral to the
sensor system, the device can be configured to be enabled and/or
disabled via a control algorithm based on the glucose measurements
and/or the sensor portion of the system. In some embodiments, the
glucose-consuming device includes a multilayer membrane. In some
embodiments, the glucose-consuming device includes control
electronics and waste management. By utilizing the energy generated
by the oxidation of glucose in a sacrificial membrane, power can be
provided to increase the battery life of a sensor system.
In some alternative embodiments, the power source can be powered by
an external power source, for example, a power source that is
physically separate from the sensor system. In some embodiments,
the external power source is configured for operative connection to
at least one of the sensor and the electronics module by radio
frequency, such as an RFID device. In one exemplary embodiment,
wherein the power source (internal to the sensor system) comprises
sufficient power to provide a bias voltage for the sensor, the
external power source is configured to interrogate and capture data
from the electronics module, for example, including providing the
power therefore using an RFID device. In this embodiment, the
sensor system is configured to deliver analyte (e.g., glucose)
information on demand, with little to no impact on battery life
(e.g., of the internal sensor system), whose size can be minimized
accordingly.
In some alternative embodiments, the power source can be powered by
an external power source, for example, a power source that is
physically separate from the sensor system. In some embodiments,
the external power source is configured for operative connection to
at least one of the sensor and the electronics module by an
inductive coupling, also referred to as an inductive coupling
device. In some embodiments, the inductive coupling device can be
used to intermittently power the power source. Additionally or
alternatively, the inductive coupling device is configured to
interrogate and capture data from the electronics module. In
general, inductive coupling, as described herein, enables power to
be transmitted to the sensor for continuous power, recharging, and
the like. In general, inductive coupling utilizes appropriately
spaced and oriented antennas (e.g., coils) on the sensor system and
external power source so as to efficiently transmit/receive power
(e.g., current) and/or data communication therebetween. One or more
coils in each of the sensor system and external power source can
provide the necessary power induction and/or data transmission.
Accordingly, the system life can be increased while reducing
battery size. In the embodiment wherein the external power source
includes inductive coupling configured to recharge the battery, the
external power source can be embodied by an external, portable,
recharging device that can be placed in a sleeping vest or belt,
for example. Additionally or alternatively, the external recharging
device can be rechargeable to avoid cycling through batteries or to
allow a more comfortable case design than large capacity batteries
can afford.
In one alternative embodiment, the sensor system does not require
power on board, and an inductive coupling, radio frequency
connection, and the like, can be provided and configured to power
the sensor, interrogate the sensor, and capture data, collectively.
In this alternative embodiment, sensor is configured to be unbiased
during its inactive state, and the external device powers the
sensor, interrogates the sensor, and captures the sensor data.
Advantageously, by implementing one or more alternative power
source embodiments as described above, the sensor system size can
be reduced (e.g., aspect ratio, mass, volume, and the like) as
compared to devices with conventional power sources, for example.
It has been discovered that the size (including aspect ratio,
volume and/or surface area) of the system can affect the function
of the system. For example, motion of the mounting unit/electronics
unit caused by external influences (e.g., bumping or other movement
on the skin) is translated to the sensor in vivo, causing motion
artifact (e.g., an effect on the signal, or the like). Accordingly,
by enabling a reduction of size, a more stable signal with overall
improved patient comfort can be achieved.
Preferably, the overall height of the sensor system, including the
housing and electronics, is no more than about 0.350, 0.300, 0.250,
0.200, 0.150, 0.100, or most preferably 0.075 inches in its
smallest dimension.
Optional temperature probe 140 is shown, wherein the temperature
probe is located on the electronics assembly or the glucose sensor
itself. The temperature probe can be used to measure ambient
temperature in the vicinity of the glucose sensor. This temperature
measurement can be used to add temperature compensation to the
calculated glucose value.
An RF module 148 is operably connected to the processor 138 and
transmits the sensor data from the sensor to a receiver within a
wireless transmission 150 via antenna 152. In some embodiments, a
second quartz crystal 154 provides the time base for the RF carrier
frequency used for data transmissions from the RF transceiver. In
some alternative embodiments, however, other mechanisms, such as
optical, infrared radiation (IR), ultrasonic, or the like, can be
used to transmit and/or receive data. In general, the RF module
includes a radio and an antenna, wherein the antenna is configured
for radiating or receiving an RF transmission. In some embodiments,
the radio and antenna are located within the electronics unit.
In some alternative embodiments, at least one of the radio and the
antenna is located remote from the electronics unit, such that the
at least one of the radio and the antenna located remotely from the
electronics unit does not dictate or limit the dimensions of the
electronics unit. In one such exemplary embodiment, the antenna is
located in or on the adhesive layer. In some embodiments, the
adhesive layer is configured for single-use and the electronics
unit is configured for reuse, whereby the remotely located antenna
(e.g., in the adhesive layer) allows for size reduction of the
reusable electronics unit and increased distribution of the antenna
(e.g., in or on the thin, flexible adhesive layer).
In some embodiments, at least one of the radio and the antenna is
located remote from the electronics unit, such that the at least
one of the radio and the antenna located remotely from the
electronics unit does not dictate or limit the dimensions of the
electronics unit. In one such exemplary embodiment, the antenna is
located in or on the housing. In some embodiments, the housing is
configured for single-use and the electronics unit is configured
for reuse, whereby the remotely located antenna (e.g., in the
housing) allows for size reduction of the reusable electronics unit
and increased distribution of the antenna (e.g., in or on the
housing). In some embodiments, the antenna extends substantially
around a periphery of the housing.
In an alternative embodiment, the antenna includes a fractal
antenna configured and arranged to maximize the length of material
that can receive or transmit electromagnetic signals within a given
total surface area, thereby enabling a compact, miniaturized
design. In general, a fractal antenna is an antenna that uses a
self-similar design to maximize the length, or increase the
perimeter (on inside sections or the outer structure), of material
that can receive or transmit electromagnetic signals within a given
total surface area or volume. Such fractal antennas are also
referred to as multilevel or space filling curves, and preferably
repeat a motif over 2 or more scale sizes or iterations. A fractal
antenna enables a miniaturized design of the sensor system,
including the housing and/or electronics unit, whether implemented
in the adhesive layer, housing, and/or electronics unit.
Advantageously, the remote location of the antenna and/or radio in
the adhesive layer and/or housing, as described above, enables a
miniaturization (e.g., reduces thickness) of the sensor system as
compared to conventional sensor systems that house their antenna
and/or radio in the same component as their sensor electronics. For
example, a remote location of the antenna and/or radio enables an
electronics unit and/or overall sensor system dimensioned and
arranged with a height of no more than about 0.250, 0.200, 0.150,
0.100, 0.075, or most preferably 0.050 inches in its smallest
dimension.
In the RF telemetry module of the preferred embodiments, the
hardware and software are designed for low power requirements to
increase the longevity of the device (for example, to enable a life
of from about 3 to about 24 months, or more) with maximum RF
transmittance from the in vivo environment to the ex vivo
environment for wholly implantable sensors (for example, a distance
of from about one to ten meters or more). Preferably, a high
frequency carrier signal of from about 402 MHz to about 433 MHz is
employed in order to maintain lower power requirements.
Additionally, in wholly implantable devices, the carrier frequency
is adapted for physiological attenuation levels, which is
accomplished by tuning the RF module in a simulated in vivo
environment to ensure RF functionality after implantation;
accordingly, the preferred glucose sensor can sustain sensor
function for 3 months, 6 months, 12 months, or 24 months or
more.
When a sensor is first implanted into host tissue, the sensor and
receiver are initialized. This is referred to as start-up mode, and
involves optionally resetting the sensor data and calibrating the
sensor 32. In selected embodiments, mating the electronics unit 16
to the mounting unit triggers a start-up mode. In other
embodiments, the start-up mode is triggered by the receiver, which
is described in more detail with reference to FIG. 19, below.
Preferably, the electronics unit 16 indicates to the receiver
(FIGS. 14 and 15) that calibration is to be initialized (or
re-initialized). The electronics unit 16 transmits a series of bits
within a transmitted data packet wherein a sensor code can be
included in the periodic transmission of the device. The status
code is used to communicate sensor status to the receiving device.
The status code can be inserted into any location in the
transmitted data packet, with or without other sensor information.
In one embodiment, the status code is designed to be unique or near
unique to an individual sensor, which can be accomplished using a
value that increments, decrements, or changes in some way after the
transmitter detects that a sensor has been removed and/or attached
to the transmitter. In an alternative embodiment, the status code
can be configured to follow a specific progression, such as a BCD
interpretation of a Gray code.
In some embodiments, the sensor electronics 132 are configured to
detect a current drop to zero in the working electrode 44
associated with removal of a sensor 32 from the host (or the
electronics unit 16 from the mounting unit 14), which can be
configured to trigger an increment of the status code. If the
incremented value reaches a maximum, it can be designed to roll
over to 0. In some embodiments, the sensor electronics are
configured to detect a voltage change cycle associated with removal
and/or re-insertion of the sensor, which can be sensed in the
counter electrode (e.g., of a three-electrode sensor), which can be
configured to trigger an increment of the status code.
In some embodiments, the sensor electronics 132 can be configured
to send a special value (for example, 0) that indicates that the
electronics unit is not attached when removal of the sensor (or
electronics unit) is detected. This special value can be used to
trigger a variety of events, for example, to halt display of
analyte values. Incrementing or decrementing routines can be used
to skip this special value.
In some embodiments, the electronics unit 16 is configured to
include additional contacts, which are designed to sense a specific
resistance, or passive value, in the sensor system while the
electronics unit is attached to the mounting unit. Preferably,
these additional contacts are configured to detect information
about a sensor, for example, whether the sensor is operatively
connected to the mounting unit, the sensor's ID, a calibration
code, or the like. For example, subsequent to sensing the passive
value, the sensor electronics can be configured to change the
sensor ID code by either mapping the value to a specific code, or
internally detecting that the code is different and adjusting the
sensor ID code in a predictable manner. As another example, the
passive value can include information on parameters specific to a
sensor (such as in vitro sensitivity information as described
elsewhere herein).
In some embodiments, the electronics unit 16 includes additional
contacts configured to communicate with a chip disposed in the
mounting unit 14. In this embodiment, the chip is designed with a
unique or near-unique signature that can be detected by the
electronics unit 16 and noted as different, and/or transmitted to
the receiver 158 as the sensor ID code.
In some embodiments, the electronics unit 16 is inductively coupled
to an RFID or similar chip in the mounting unit 14. In this
embodiment, the RFID tag uniquely identifies the sensor 32 and
allows the transmitter to adjust the sensor ID code accordingly
and/or to transmit the unique identifier to the receiver 158.
In some situations, it can be desirable to wait an amount of time
after insertion of the sensor to allow the sensor to equilibrate in
vivo, also referred to as "break-in." Accordingly, the sensor
electronics can be configured to aid in decreasing the break-in
time of the sensor by applying different voltage settings (for
example, starting with a higher voltage setting and then reducing
the voltage setting) to speed the equilibration process.
In some situations, the sensor may not properly deploy, connect to,
or otherwise operate as intended. Accordingly, the sensor
electronics can be configured such that if the current obtained
from the working electrode, or the subsequent conversion of the
current into digital counts, for example, is outside of an
acceptable threshold, then the sensor is marked with an error flag,
or the like. The error flag can be transmitted to the receiver to
instruct the user to reinsert a new sensor, or to implement some
other error correction.
The above-described detection and transmission methods can be
advantageously employed to minimize or eliminate human interaction
with the sensor, thereby minimizing human error and/or
inconvenience. Additionally, the sensors of preferred embodiments
do not require that the receiver be in proximity to the transmitter
during sensor insertion. Any one or more of the above described
methods of detecting and transmitting insertion of a sensor and/or
electronics unit can be combined or modified, as is appreciated by
one skilled in the art.
Receiver
FIG. 14 is a perspective view of a sensor system, including
wireless communication between a sensor and a receiver. Preferably
the electronics unit 16 is wirelessly connected to a receiver 158
via one- or two-way RF transmissions or the like. However, a wired
connection is also contemplated. The receiver 158 provides much of
the processing and display of the sensor data, and can be
selectively worn and/or removed at the host's convenience. Thus,
the sensor system 10 can be discreetly worn, and the receiver 158,
which provides much of the processing and display of the sensor
data, can be selectively worn and/or removed at the host's
convenience. Particularly, the receiver 158 includes programming
for retrospectively and/or prospectively initiating a calibration,
converting sensor data, updating the calibration, evaluating
received reference and sensor data, and evaluating the calibration
for the analyte sensor, such as described in more detail with
reference to U.S. Patent Publication No. US-2005-0027463-A1.
Receiver Electronics
FIG. 15A is a block diagram that illustrates the configuration of
the medical device in one embodiment, including a continuous
analyte sensor, a receiver, and an external device. In general, the
analyte sensor system is any sensor configuration that provides an
output signal indicative of a concentration of an analyte (e.g.,
invasive, minimally-invasive, and/or non-invasive sensors as
described above). The output signal is sent to a receiver 158 and
received by an input module 174, which is described in more detail
below. The output signal is typically a raw data stream that is
used to provide a useful value of the measured analyte
concentration to a patient or a doctor, for example. In some
embodiments, the raw data stream can be continuously or
periodically algorithmically smoothed or otherwise modified to
diminish outlying points that do not accurately represent the
analyte concentration, for example due to signal noise or other
signal artifacts, such as described in U.S. Pat. No. 6,931,327.
Referring again to FIG. 15A, the receiver 158, which is operatively
linked to the sensor system 10, receives a data stream from the
sensor system 10 via the input module 174. In one embodiment, the
input module includes a quartz crystal operably connected to an RF
transceiver (not shown) that together function to receive and
synchronize data streams from the sensor system 10. However, the
input module 174 can be configured in any manner that is capable of
receiving data from the sensor. Once received, the input module 174
sends the data stream to a processor 176 that processes the data
stream, such as is described in more detail below.
The processor 176 is the central control unit that performs the
processing, such as storing data, analyzing data streams,
calibrating analyte sensor data, estimating analyte values,
comparing estimated analyte values with time corresponding measured
analyte values, analyzing a variation of estimated analyte values,
downloading data, and controlling the user interface by providing
analyte values, prompts, messages, warnings, alarms, or the like.
The processor includes hardware and software that performs the
processing described herein, for example flash memory provides
permanent or semi-permanent storage of data, storing data such as
sensor ID, receiver ID, and programming to process data streams
(for example, programming for performing estimation and other
algorithms described elsewhere herein) and random access memory
(RAM) stores the system's cache memory and is helpful in data
processing.
Preferably, the input module 174 or processor module 176 performs a
Cyclic Redundancy Check (CRC) to verify data integrity, with or
without a method of recovering the data if there is an error. In
some embodiments, error correction techniques such as those that
use Hamming codes or Reed-Solomon encoding/decoding methods are
employed to correct for errors in the data stream. In one
alternative embodiment, an iterative decoding technique is
employed, wherein the decoding is processed iteratively (e.g., in a
closed loop) to determine the most likely decoded signal. This type
of decoding can allow for recovery of a signal that is as low as
0.5 dB above the noise floor, which is in contrast to conventional
non-iterative decoding techniques (such as Reed-Solomon), which
requires approximately 3 dB or about twice the signal power to
recover the same signal (e.g., a turbo code).
An output module 178, which is integral with and/or operatively
connected with the processor 176, includes programming for
generating output based on the data stream received from the sensor
system 10 and its processing incurred in the processor 176. In some
embodiments, output is generated via a user interface 160.
The user interface 160 comprises a keyboard 162, speaker 164,
vibrator 166, backlight 168, liquid crystal display (LCD) screen
170, and one or more buttons 172. The components that comprise the
user interface 160 include controls to allow interaction of the
user with the receiver. The keyboard 162 can allow, for example,
input of user information about himself/herself, such as mealtime,
exercise, insulin administration, customized therapy
recommendations, and reference analyte values. The speaker 164 can
produce, for example, audible signals or alerts for conditions such
as present and/or estimated hyperglycemic or hypoglycemic
conditions in a person with diabetes. The vibrator 166 can provide,
for example, tactile signals or alerts for reasons such as
described with reference to the speaker, above. The backlight 168
can be provided, for example, to aid the user in reading the LCD
170 in low light conditions. The LCD 170 can be provided, for
example, to provide the user with visual data output, such as is
described in U.S. Patent Publication No. US-2005-0203360-A1. FIGS.
15B to 15D illustrate some additional visual displays that can be
provided on the screen 170. In some embodiments, the LCD is a
touch-activated screen, enabling each selection by a user, for
example, from a menu on the screen. The buttons 172 can provide for
toggle, menu selection, option selection, mode selection, and
reset, for example. In some alternative embodiments, a microphone
can be provided to allow for voice-activated control.
In some embodiments, prompts or messages can be displayed on the
user interface to convey information to the user, such as reference
outlier values, requests for reference analyte values, therapy
recommendations, deviation of the measured analyte values from the
estimated analyte values, or the like. Additionally, prompts can be
displayed to guide the user through calibration or trouble-shooting
of the calibration.
Additionally, data output from the output module 178 can provide
wired or wireless, one- or two-way communication between the
receiver 158 and an external device 180. The external device 180
can be any device that wherein interfaces or communicates with the
receiver 158. In some embodiments, the external device 180 is a
computer, and the receiver 158 is able to download historical data
for retrospective analysis by the patient or physician, for
example. In some embodiments, the external device 180 is a modem or
other telecommunications station, and the receiver 158 is able to
send alerts, warnings, emergency messages, or the like, via
telecommunication lines to another party, such as a doctor or
family member. In some embodiments, the external device 180 is an
insulin pen, and the receiver 158 is able to communicate therapy
recommendations, such as insulin amount and time to the insulin
pen. In some embodiments, the external device 180 is an insulin
pump, and the receiver 158 is able to communicate therapy
recommendations, such as insulin amount and time to the insulin
pump. The external device 180 can include other technology or
medical devices, for example pacemakers, implanted analyte sensor
patches, other infusion devices, telemetry devices, or the
like.
The user interface 160, including keyboard 162, buttons 172, a
microphone (not shown), and the external device 180, can be
configured to allow input of data. Data input can be helpful in
obtaining information about the patient (for example, meal time,
exercise, or the like), receiving instructions from a physician
(for example, customized therapy recommendations, targets, or the
like), and downloading software updates, for example. Keyboard,
buttons, touch-screen, and microphone are all examples of
mechanisms by which a user can input data directly into the
receiver. A server, personal computer, personal digital assistant,
insulin pump, and insulin pen are examples of external devices that
can provide useful information to the receiver. Other devices
internal or external to the sensor that measure other aspects of a
patient's body (for example, temperature sensor, accelerometer,
heart rate monitor, oxygen monitor, or the like) can be used to
provide input helpful in data processing. In one embodiment, the
user interface can prompt the patient to select an activity most
closely related to their present activity, which can be helpful in
linking to an individual's physiological patterns, or other data
processing. In another embodiment, a temperature sensor and/or
heart rate monitor can provide information helpful in linking
activity, metabolism, and glucose excursions of an individual.
While a few examples of data input have been provided here, a
variety of information can be input, which can be helpful in data
processing.
FIG. 15B is an illustration of an LCD screen 170 showing continuous
and single point glucose information in the form of a trend graph
184 and a single numerical value 186. The trend graph shows upper
and lower boundaries 182 representing a target range between which
the host should maintain his/her glucose values. Preferably, the
receiver is configured such that these boundaries 182 can be
configured or customized by a user, such as the host or a care
provider. By providing visual boundaries 182, in combination with
continuous analyte values over time (e.g., a trend graph 184), a
user may better learn how to control his/her analyte concentration
(e.g., a person with diabetes may better learn how to control
his/her glucose concentration) as compared to single point (single
numerical value 186) alone. Although FIG. 15B illustrates a 1-hour
trend graph (e.g., depicted with a time range 188 of 1-hour), a
variety of time ranges can be represented on the screen 170, for
example, 3-hour, 9-hour, 1-day, and the like.
FIG. 15C is an illustration of an LCD screen 170 showing a low
alert screen that can be displayed responsive to a host's analyte
concentration falling below a lower boundary (see boundaries 182).
In this exemplary screen, a host's glucose concentration has fallen
to 55 mg/dL, which is below the lower boundary set in FIG. 15B, for
example. The arrow 190 represents the direction of the analyte
trend, for example, indicating that the glucose concentration is
continuing to drop. The annotation 192 ("LOW") is helpful in
immediately and clearly alerting the host that his/her glucose
concentration has dropped below a preset limit, and what may be
considered to be a clinically safe value, for example. FIG. 15D is
an illustration of an LCD screen 170 showing a high alert screen
that can be displayed responsive to a host's analyte concentration
rising above an upper boundary (see boundaries 182). In this
exemplary screen, a host's glucose concentration has risen to 200
mg/dL, which is above a boundary set by the host, thereby
triggering the high alert screen. The arrow 190 represents the
direction of the analyte trend, for example, indicating that the
glucose concentration is continuing to rise. The annotation 192
("HIGH") is helpful in immediately and clearly alerting the host
that his/her glucose concentration has above a preset limit, and
what may be considered to be a clinically safe value, for
example.
Although a few exemplary screens are depicted herein, a variety of
screens can be provided for illustrating any of the information
described in the preferred embodiments, as well as additional
information. A user can toggle between these screens (e.g., using
buttons 172) and/or the screens can be automatically displayed
responsive to programming within the receiver 158, and can be
simultaneously accompanied by another type of alert (audible or
tactile, for example).
Algorithms
FIG. 16A provides a flow chart 200 that illustrates the initial
calibration and data output of the sensor data in one embodiment,
wherein calibration is responsive to reference analyte data.
Initial calibration, also referred to as start-up mode, occurs at
the initialization of a sensor, for example, the first time an
electronics unit is used with a particular sensor. In certain
embodiments, start-up calibration is triggered when the system
determines that it can no longer remain in normal or suspended
mode, which is described in more detail with reference to FIG.
19.
Calibration of an analyte sensor comprises data processing that
converts sensor data signal into an estimated analyte measurement
that is meaningful to a user. Accordingly, a reference analyte
value is used to calibrate the data signal from the analyte
sensor.
At block 202, a sensor data receiving module, also referred to as
the sensor data module, receives sensor data (e.g., a data stream),
including one or more time-spaced sensor data points, from the
sensor 32 via the receiver 158, which can be in wired or wireless
communication with the sensor 32. The sensor data point(s) can be
smoothed (filtered) in certain embodiments using a filter, for
example, a finite impulse response (FIR) or infinite impulse
response (IIR) filter. During the initialization of the sensor,
prior to initial calibration, the receiver receives and stores the
sensor data, however it can be configured to not display any data
to the user until initial calibration and, optionally,
stabilization of the sensor has been established. In some
embodiments, the data stream can be evaluated to determine sensor
break-in (equilibration of the sensor in vitro or in vivo).
At block 204, a reference data receiving module, also referred to
as the reference input module, receives reference data from a
reference analyte monitor, including one or more reference data
points. In one embodiment, the reference analyte points can
comprise results from a self-monitored blood analyte test (e.g.,
finger stick test). For example, the user can administer a
self-monitored blood analyte test to obtain an analyte value (e.g.,
point) using any known analyte sensor, and then enter the numeric
analyte value into the computer system. Alternatively, a
self-monitored blood analyte test is transferred into the computer
system through a wired or wireless connection to the receiver (e.g.
computer system) so that the user simply initiates a connection
between the two devices, and the reference analyte data is passed
or downloaded between the self-monitored blood analyte test and the
receiver. In yet another embodiment, the self-monitored analyte
test (e.g., SMBG) is integral with the receiver so that the user
simply provides a blood sample to the receiver, and the receiver
runs the analyte test to determine a reference analyte value. U.S.
Patent Publication No. US-2005-0154271-A1 describes some systems
and methods for integrating a reference analyte monitor into a
receiver for a continuous analyte sensor.
In some alternative embodiments, the reference data is based on
sensor data from another substantially continuous analyte sensor,
e.g., a transcutaneous analyte sensor described herein, or another
type of suitable continuous analyte sensor. In an embodiment
employing a series of two or more transcutaneous (or other
continuous) sensors, the sensors can be employed so that they
provide sensor data in discrete or overlapping periods. In such
embodiments, the sensor data from one continuous sensor can be used
to calibrate another continuous sensor, or be used to confirm the
validity of a subsequently employed continuous sensor.
In some embodiments, reference data can be subjected to "outlier
detection" wherein the accuracy of a received reference analyte
data is evaluated as compared to time-corresponding sensor data. In
one embodiment, the reference data is compared to the sensor data
on a modified Clarke Error Grid (e.g., a test similar to the Clarke
Error Grid except the boundaries between the different regions are
modified slightly) to determine if the data falls within a
predetermined threshold. If the data is not within the
predetermined threshold, then the receiver can be configured to
request additional reference analyte data. If the additional
reference analyte data confirms (e.g., closely correlates to) the
first reference analyte data, then the first and second reference
values are assumed to be accurate and calibration of the sensor is
adjusted or re-initialized. Alternatively, if the second reference
analyte value falls within the predetermined threshold, then the
first reference analyte value is assumed to be an outlier and the
second reference analyte value is used by the algorithm(s) instead.
In one alternative embodiments of outlier detection, projection is
used to estimate an expected analyte value, which is compared with
the actual value and a delta evaluated for substantial
correspondence. However, other methods of outlier detection are
possible.
Certain acceptability parameters can be set for reference values
received from the user. For example, in one embodiment, the
receiver can be configured to only accept reference analyte values
of from about 40 mg/dL to about 400 mg/dL.
At block 206, a data matching module, also referred to as the
processor module, matches reference data (e.g., one or more
reference analyte data points) with substantially time
corresponding sensor data (e.g., one or more sensor data points) to
provide one or more matched data pairs. One reference data point
can be matched to one time corresponding sensor data point to form
a matched data pair. Alternatively, a plurality of reference data
points can be averaged (e.g., equally or non-equally weighted
average, mean-value, median, or the like) and matched to one time
corresponding sensor data point to form a matched data pair, one
reference data point can be matched to a plurality of time
corresponding sensor data points averaged to form a matched data
pair, or a plurality of reference data points can be averaged and
matched to a plurality of time corresponding sensor data points
averaged to form a matched data pair.
In one embodiment, time corresponding sensor data comprises one or
more sensor data points that occur from about 0 minutes to about 20
minutes after the reference analyte data time stamp (e.g., the time
that the reference analyte data is obtained). In one embodiment, a
5-minute time delay is chosen to compensate for a system time-lag
(e.g., the time necessary for the analyte to diffusion through a
membrane(s) of an analyte sensor). In alternative embodiments, the
time corresponding sensor value can be greater than or less than
that of the above-described embodiment, for example .+-.60 minutes.
Variability in time correspondence of sensor and reference data can
be attributed to, for example, a longer or shorter time delay
introduced by the data smoothing filter, or if the configuration of
the analyte sensor incurs a greater or lesser physiological time
lag.
In some implementations of the sensor, the reference analyte data
is obtained at a time that is different from the time that the data
is input into the receiver. Accordingly, the "time stamp" of the
reference analyte (e.g., the time at which the reference analyte
value was obtained) is not the same as the time at which the
receiver obtained the reference analyte data. Therefore, some
embodiments include a time stamp requirement that ensures that the
receiver stores the accurate time stamp for each reference analyte
value, that is, the time at which the reference value was actually
obtained from the user.
In certain embodiments, tests are used to evaluate the best-matched
pair using a reference data point against individual sensor values
over a predetermined time period (e.g., about 30 minutes). In one
such embodiment, the reference data point is matched with sensor
data points at 5-minute intervals and each matched pair is
evaluated. The matched pair with the best correlation can be
selected as the matched pair for data processing. In some
alternative embodiments, matching a reference data point with an
average of a plurality of sensor data points over a predetermined
time period can be used to form a matched pair.
At block 208, a calibration set module, also referred to as the
processor module, forms an initial calibration set from a set of
one or more matched data pairs, which are used to determine the
relationship between the reference analyte data and the sensor
analyte data. The matched data pairs, which make up the initial
calibration set, can be selected according to predetermined
criteria. The criteria for the initial calibration set can be the
same as, or different from, the criteria for the updated
calibration sets. In certain embodiments, the number (n) of data
pair(s) selected for the initial calibration set is one. In other
embodiments, n data pairs are selected for the initial calibration
set wherein n is a function of the frequency of the received
reference data points. In various embodiments, two data pairs make
up the initial calibration set or six data pairs make up the
initial calibration set. In an embodiment wherein a substantially
continuous analyte sensor provides reference data, numerous data
points are used to provide reference data from more than 6 data
pairs (e.g., dozens or even hundreds of data pairs). In one
exemplary embodiment, a substantially continuous analyte sensor
provides 288 reference data points per day (every five minutes for
twenty-four hours), thereby providing an opportunity for a matched
data pair 288 times per day, for example. While specific numbers of
matched data pairs are referred to in the preferred embodiments,
any suitable number of matched data pairs per a given time period
can be employed.
In certain embodiments, the data pairs are selected only within a
certain analyte value threshold, for example wherein the reference
analyte value is from about 40 mg/dL to about 400 mg/dL. In certain
embodiments, the data pairs that form the initial calibration set
are selected according to their time stamp, for example, by waiting
a predetermined "break-in" time period after implantation, the
stability of the sensor data can be increased. In certain
embodiments, the data pairs that form the initial calibration set
are spread out over a predetermined time period, for example, a
period of two hours or more. In certain embodiments, the data pairs
that form the initial calibration set are spread out over a
predetermined glucose range, for example, spread out over a range
of at least 90 mg/dL or more.
At block 210, a conversion function module, also referred to as the
processor module, uses the calibration set to create a conversion
function. The conversion function substantially defines the
relationship between the reference analyte data and the analyte
sensor data.
A variety of known methods can be used with the preferred
embodiments to create the conversion function from the calibration
set. In one embodiment, wherein a plurality of matched data points
form the calibration set, a linear least squares regression is used
to calculate the conversion function; for example, this regression
calculates a slope and an offset using the equation y=mx+b. A
variety of regression or other conversion schemes can be
implemented herein.
In some alternative embodiments, the sensor is calibrated with a
single-point through the use of a dual-electrode system to simplify
sensor calibration. In one such dual-electrode system, a first
electrode functions as a hydrogen peroxide sensor including a
membrane system containing glucose-oxidase disposed thereon, which
operates as described herein. A second electrode is a hydrogen
peroxide sensor that is configured similar to the first electrode,
but with a modified membrane system (with the enzyme domain
removed, for example). This second electrode provides a signal
composed mostly of the baseline signal, b.
In some dual-electrode systems, the baseline signal is
(electronically or digitally) subtracted from the glucose signal to
obtain a glucose signal substantially without baseline.
Accordingly, calibration of the resultant difference signal can be
performed by solving the equation y=mx with a single paired
measurement. Calibration of the implanted sensor in this
alternative embodiment can be made less dependent on the
values/range of the paired measurements, less sensitive to error in
manual blood glucose measurements, and can facilitate the sensor's
use as a primary source of glucose information for the user. U.S.
Patent Publication No. US-2005-0143635-A1 describes systems and
methods for subtracting the baseline from a sensor signal.
In some alternative dual-electrode system embodiments, the analyte
sensor is configured to transmit signals obtained from each
electrode separately (e.g., without subtraction of the baseline
signal). In this way, the receiver can process these signals to
determine additional information about the sensor and/or analyte
concentration. For example, by comparing the signals from the first
and second electrodes, changes in baseline and/or sensitivity can
be detected and/or measured and used to update calibration (e.g.,
without the use of a reference analyte value). In one such example,
by monitoring the corresponding first and second signals over time,
an amount of signal contributed by baseline can be measured. In
another such example, by comparing fluctuations in the correlating
signals over time, changes in sensitivity can be detected and/or
measured.
In some alternative embodiments, a regression equation y=mx+b is
used to calculate the conversion function; however, prior
information can be provided for m and/or b, thereby enabling
calibration to occur with fewer paired measurements. In one
calibration technique, prior information (e.g., obtained from in
vivo or in vitro tests) determines a sensitivity of the sensor
and/or the baseline signal of the sensor by analyzing sensor data
from measurements taken by the sensor (e.g., prior to inserting the
sensor). For example, if there exists a predictive relationship
between in vitro sensor parameters and in vivo parameters, then
this information can be used by the calibration procedure. For
example, if a predictive relationship exists between in vitro
sensitivity and in vivo sensitivity, m.apprxeq.f(m.sub.in vitro),
then the predicted m can be used, along with a single matched pair,
to solve for b (b=y-mx). If, in addition, b can be assumed=0, for
example with a dual-electrode configuration that enables
subtraction of the baseline from the signal such as described
above, then both m and b are known a priori, matched pairs are not
needed for calibration, and the sensor can be completely calibrated
e.g. without the need for reference analyte values (e.g. values
obtained after implantation in vivo.)
In another alternative embodiment, prior information can be
provided to guide or validate the baseline (b) and/or sensitivity
(m) determined from the regression analysis. In this embodiment,
boundaries can be set for the regression line that defines the
conversion function such that working sensors are calibrated
accurately and easily (with two points), and non-working sensors
are prevented from being calibrated. If the boundaries are drawn
too tightly, a working sensor may not enter into calibration.
Likewise, if the boundaries are drawn too loosely, the scheme can
result in inaccurate calibration or can permit non-working sensors
to enter into calibration. For example, subsequent to performing
regression, the resulting slope and/or baseline are tested to
determine whether they fall within a predetermined acceptable
threshold (boundaries). These predetermined acceptable boundaries
can be obtained from in vivo or in vitro tests (e.g., by a
retrospective analysis of sensor sensitivities and/or baselines
collected from a set of sensors/patients, assuming that the set is
representative of future data).
If the slope and/or baseline fall within the predetermined
acceptable boundaries, then the regression is considered acceptable
and processing continues to the next step (e.g., block 212).
Alternatively, if the slope and/or baseline fall outside the
predetermined acceptable boundaries, steps can be taken to either
correct the regression or fail-safe such that a system will not
process or display errant data. This can be useful in situations
wherein regression results in errant slope or baseline values. For
example, when points (matched pairs) used for regression are too
close in value, the resulting regression statistically is less
accurate than when the values are spread farther apart. As another
example, a sensor that is not properly deployed or is damaged
during deployment can yield a skewed or errant baseline signal.
In some alternative embodiments, the sensor system does not require
initial and/or update calibration by the host; in these alternative
embodiments, also referred to as "zero-point calibration"
embodiments, use of the sensor system without requiring a reference
analyte measurement for initial and/or update calibration is
enabled. In general, the systems and methods of the preferred
embodiments provide for stable and repeatable sensor manufacture,
particularly when tightly controlled manufacturing processes are
utilized. Namely, a batch of sensors of the preferred embodiments
can be designed with substantially the same baseline (b) and/or
sensitivity (m) (+/-10%) when tested in vitro. Additionally, the
sensor of the preferred embodiments can be designed for repeatable
m and b in vivo. Thus, an initial calibration factor (conversion
function) can be programmed into the sensor (sensor electronics
and/or receiver electronics) that enables conversion of raw sensor
data into calibrated sensor data solely using information obtained
prior to implantation (namely, initial calibration does not require
a reference analyte value). Additionally, to obviate the need for
recalibration (update calibration) during the life of the sensor,
the sensor is designed to minimize drift of the sensitivity and/or
baseline over time in vivo. Accordingly, the preferred embodiments
can be manufactured for zero point calibration.
FIG. 16B is a graph that illustrates one example of using prior
information for slope and baseline. The x-axis represents reference
glucose data (blood glucose) from a reference glucose source in
mg/dL; the y-axis represents sensor data from a transcutaneous
glucose sensor of the preferred embodiments in counts. An upper
boundary line 215 is a regression line that represents an upper
boundary of "acceptability" in this example; the lower boundary
line 216 is a regression line that represents a lower boundary of
"acceptability" in this example. The boundary lines 215, 216 were
obtained from retrospective analysis of in vivo sensitivities and
baselines of glucose sensors as described in the preferred
embodiments.
A plurality of matched data pairs 217 represents data pairs in a
calibration set obtained from a glucose sensor as described in the
preferred embodiments. The matched data pairs are plotted according
to their sensor data and time-corresponding reference glucose data.
A regression line 218 represents the result of regressing the
matched data pairs 217 using least squares regression. In this
example, the regression line falls within the upper and lower
boundaries 215, 216 indicating that the sensor calibration is
acceptable.
However, if the slope and/or baseline had fallen outside the
predetermined acceptable boundaries, which would be illustrated in
this graph by a line that crosses the upper and/or lower boundaries
215, 216, then the system is configured to assume a baseline value
and re-run the regression (or a modified version of the regression)
with the assumed baseline, wherein the assumed baseline value is
derived from in vivo or in vitro testing. Subsequently, the newly
derived slope and baseline are again tested to determine whether
they fall within the predetermined acceptable boundaries.
Similarly, the processing continues in response to the results of
the boundary test. In general, for a set of matched pairs (e.g.,
calibration set), regression lines with higher slope (sensitivity)
have a lower baseline and regression lines with lower slope
(sensitivity) have a higher baseline. Accordingly, the step of
assuming a baseline and testing against boundaries can be repeated
using a variety of different assumed baselines based on the
baseline, sensitivity, in vitro testing, and/or in vivo testing.
For example, if a boundary test fails due to high sensitivity, then
a higher baseline is assumed and the regression re-run and
boundary-tested. It is preferred that after about two iterations of
assuming a baseline and/or sensitivity and running a modified
regression, the system assumes an error has occurred (if the
resulting regression lines fall outside the boundaries) and
fail-safe. The term "fail-safe" includes modifying the system
processing and/or display of data responsive to a detected error
avoid reporting of inaccurate or clinically irrelevant analyte
values.
In these various embodiments utilizing an additional electrode,
prior information (e.g., in vitro or in vivo testing), signal
processing, or other information for assisting in the calibration
process can be used alone or in combination to reduce or eliminate
the dependency of the calibration on reference analyte values
obtained by the host.
At block 212, a sensor data transformation module uses the
conversion function to transform sensor data into substantially
real-time analyte value estimates, also referred to as calibrated
data, or converted sensor data, as sensor data is continuously (or
intermittently) received from the sensor. For example, the sensor
data, which can be provided to the receiver in "counts," is
translated in to estimate analyte value(s) in mg/dL. In other
words, the offset value at any given point in time can be
subtracted from the raw value (e.g., in counts) and divided by the
slope to obtain the estimate analyte value:
.times..times. ##EQU00001##
In some alternative embodiments, the sensor and/or reference
analyte values are stored in a database for retrospective
analysis.
At block 214, an output module provides output to the user via the
user interface. The output is representative of the estimated
analyte value, which is determined by converting the sensor data
into a meaningful analyte value. User output can be in the form of
a numeric estimated analyte value, an indication of directional
trend of analyte concentration, and/or a graphical representation
of the estimated analyte data over a period of time, for example.
Other representations of the estimated analyte values are also
possible, for example audio and tactile.
In some embodiments, annotations are provided on the graph; for
example, bitmap images are displayed thereon, which represent
events experienced by the host. For example, information about
meals, insulin, exercise, sensor insertion, sleep, and the like,
can be obtained by the receiver (by user input or receipt of a
transmission from another device) and displayed on the graphical
representation of the host's glucose over time. It is believed that
illustrating a host's life events matched with a host's glucose
concentration over time can be helpful in educating the host to his
or her metabolic response to the various events.
In yet another alternative embodiment, the sensor utilizes one or
more additional electrodes to measure an additional analyte. Such
measurements can provide a baseline or sensitivity measurement for
use in calibrating the sensor. Furthermore, baseline and/or
sensitivity measurements can be used to trigger events such as
digital filtering of data or suspending display of data, all of
which are described in more detail in U.S. Patent Publication No.
US-2005-0143635-A1.
FIG. 17 provides a flow chart 220 that illustrates the evaluation
of reference and/or sensor data for statistical, clinical, and/or
physiological acceptability in one embodiment. Although some
acceptability tests are disclosed herein, any known statistical,
clinical, physiological standards and methodologies can be applied
to evaluate the acceptability of reference and sensor analyte
data.
One cause for discrepancies in reference and sensor data is a
sensitivity drift that can occur over time, when a sensor is
inserted into a host and cellular invasion of the sensor begins to
block transport of the analyte to the sensor, for example.
Therefore, it can be advantageous to validate the acceptability of
converted sensor data against reference analyte data, to determine
if a drift of sensitivity has occurred and whether the calibration
should be updated.
In one embodiment, the reference analyte data is evaluated with
respect to substantially time corresponding converted sensor data
to determine the acceptability of the matched pair. For example,
clinical acceptability considers a deviation between time
corresponding analyte measurements (for example, data from a
glucose sensor and data from a reference glucose monitor) and the
risk (for example, to the decision making of a person with
diabetes) associated with that deviation based on the glucose value
indicated by the sensor and/or reference data. Evaluating the
clinical acceptability of reference and sensor analyte data, and
controlling the user interface dependent thereon, can minimize
clinical risk. Preferably, the receiver evaluates clinical
acceptability each time reference data is obtained.
After initial calibration, such as is described in more detail with
reference to FIG. 16, the sensor data receiving module 222 receives
substantially continuous sensor data (e.g., a data stream) via a
receiver and converts that data into estimated analyte values. As
used herein, the term "substantially continuous" is a broad term
and is used in its ordinary sense, without limitation, to refer to
a data stream of individual measurements taken at time intervals
(e.g., time-spaced) ranging from fractions of a second up to, e.g.,
1, 2, or 5 minutes or more. As sensor data is continuously
converted, it can be occasionally recalibrated in response to
changes in sensor sensitivity (drift), for example. Initial
calibration and re-calibration of the sensor require a reference
analyte value. Accordingly, the receiver can receive reference
analyte data at any time for appropriate processing.
At block 222, the reference data receiving module, also referred to
as the reference input module, receives reference analyte data from
a reference analyte monitor. In one embodiment, the reference data
comprises one analyte value obtained from a reference monitor. In
some alternative embodiments however, the reference data includes a
set of analyte values entered by a user into the interface and
averaged by known methods, such as are described elsewhere herein.
In some alternative embodiments, the reference data comprises a
plurality of analyte values obtained from another continuous
analyte sensor.
The reference data can be pre-screened according to environmental
and physiological issues, such as time of day, oxygen
concentration, postural effects, and patient-entered environmental
data. In one exemplary embodiment, wherein the sensor comprises an
implantable glucose sensor, an oxygen sensor within the glucose
sensor is used to determine if sufficient oxygen is being provided
to successfully complete the necessary enzyme and electrochemical
reactions for accurate glucose sensing. In another exemplary
embodiment, the patient is prompted to enter data into the user
interface, such as meal times and/or amount of exercise, which can
be used to determine likelihood of acceptable reference data. In
yet another exemplary embodiment, the reference data is matched
with time-corresponding sensor data, which is then evaluated on a
modified clinical error grid to determine its clinical
acceptability.
Some evaluation data, such as described in the paragraph above, can
be used to evaluate an optimum time for reference analyte
measurement. Correspondingly, the user interface can then prompt
the user to provide a reference data point for calibration within a
given time period. Consequently, because the receiver proactively
prompts the user during optimum calibration times, the likelihood
of error due to environmental and physiological limitations can
decrease and consistency and acceptability of the calibration can
increase.
At block 224, the evaluation module, also referred to as
acceptability module, evaluates newly received reference data. In
one embodiment, the evaluation module evaluates the clinical
acceptability of newly received reference data and time
corresponding converted sensor data (new matched data pair). In one
embodiment, a clinical acceptability evaluation module 224 matches
the reference data with a substantially time corresponding
converted sensor value, and determines the Clarke Error Grid
coordinates. In this embodiment, matched pairs that fall within the
A and B regions of the Clarke Error Grid are considered clinically
acceptable, while matched pairs that fall within the C, D, and E
regions of the Clarke Error Grid are not considered clinically
acceptable.
A variety of other known methods of evaluating clinical
acceptability can be utilized. In one alternative embodiment, the
Consensus Grid is used to evaluate the clinical acceptability of
reference and sensor data. In another alternative embodiment, a
mean absolute difference calculation can be used to evaluate the
clinical acceptability of the reference data. In another
alternative embodiment, the clinical acceptability can be evaluated
using any relevant clinical acceptability test, such as a known
grid (e.g., Clarke Error or Consensus), and additional parameters,
such as time of day and/or the increase or decreasing trend of the
analyte concentration. In another alternative embodiment, a rate of
change calculation can be used to evaluate clinical acceptability.
In yet another alternative embodiment, wherein the received
reference data is in substantially real time, the conversion
function could be used to predict an estimated glucose value at a
time corresponding to the time stamp of the reference analyte value
(this can be required due to a time lag of the sensor data such as
described elsewhere herein). Accordingly, a threshold can be set
for the predicted estimated glucose value and the reference analyte
value disparity, if any. In some alternative embodiments, the
reference data is evaluated for physiological and/or statistical
acceptability as described in more detail elsewhere herein.
At decision block 226, results of the evaluation are assessed. If
acceptability is determined, then processing continues to block 228
to re-calculate the conversion function using the new matched data
pair in the calibration set.
At block 228, the conversion function module re-creates the
conversion function using the new matched data pair associated with
the newly received reference data. In one embodiment, the
conversion function module adds the newly received reference data
(e.g., including the matched sensor data) into the calibration set,
and recalculates the conversion function accordingly. In
alternative embodiments, the conversion function module displaces
the oldest, and/or least concordant matched data pair from the
calibration set, and recalculates the conversion function
accordingly.
At block 230, the sensor data transformation module uses the new
conversion function (from block 228) to continually (or
intermittently) convert sensor data into estimated analyte values,
also referred to as calibrated data, or converted sensor data, such
as is described in more detail above.
At block 232, an output module provides output to the user via the
user interface. The output is representative of the estimated
analyte value, which is determined by converting the sensor data
into a meaningful analyte value. User output can be in the form of
a numeric estimated analyte value, an indication of directional
trend of analyte concentration, and/or a graphical representation
of the estimated analyte data over a period of time, for example.
Other representations of the estimated analyte values are also
possible, for example audio and tactile.
If, however, acceptability is determined at decision block 226 as
negative (unacceptable), then the processing progresses to block
234 to adjust the calibration set. In one embodiment of a
calibration set adjustment, the conversion function module removes
one or more oldest matched data pair(s) and recalculates the
conversion function accordingly. In an alternative embodiment, the
conversion function module removes the least concordant matched
data pair from the calibration set, and recalculates the conversion
function accordingly.
At block 236, the conversion function module re-creates the
conversion function using the adjusted calibration set. While not
wishing to be bound by theory, it is believed that removing the
least concordant and/or oldest matched data pair(s) from the
calibration set can reduce or eliminate the effects of sensor
sensitivity drift over time, adjusting the conversion function to
better represent the current sensitivity of the sensor.
At block 224, the evaluation module re-evaluates the acceptability
of newly received reference data with time corresponding converted
sensor data that has been converted using the new conversion
function (block 236). The flow continues to decision block 238 to
assess the results of the evaluation, such as described with
reference to decision block 226, above. If acceptability is
determined, then processing continues to block 230 to convert
sensor data using the new conversion function and continuously
display calibrated sensor data on the user interface.
If, however, acceptability is determined at decision block 226 as
negative, then the processing loops back to block 234 to adjust the
calibration set once again. This process can continue until the
calibration set is no longer sufficient for calibration, for
example, when the calibration set includes only one or no matched
data pairs with which to create a conversion function. In this
situation, the system can return to the initial calibration or
start-up mode, which is described in more detail with reference to
FIGS. 16 and 19, for example. Alternatively, the process can
continue until inappropriate matched data pairs have been
sufficiently purged and acceptability is positively determined.
In alternative embodiments, the acceptability is determined by a
quality evaluation, for example, calibration quality can be
evaluated by determining the statistical association of data that
forms the calibration set, which determines the confidence
associated with the conversion function used in calibration and
conversion of raw sensor data into estimated analyte values. See,
e.g., U.S. Patent Publication No. US-2005-0027463-A1.
Alternatively, each matched data pair can be evaluated based on
clinical or statistical acceptability such as described above;
however, when a matched data pair does not pass the evaluation
criteria, the system can be configured to ask for another matched
data pair from the user. In this way, a secondary check can be used
to determine whether the error is more likely due to the reference
glucose value or to the sensor value. If the second reference
glucose value substantially correlates to the first reference
glucose value, it can be presumed that the reference glucose value
is more accurate and the sensor values are errant. Some reasons for
errancy of the sensor values include a shift in the baseline of the
signal or noise on the signal due to low oxygen, for example. In
such cases, the system can be configured to re-initiate calibration
using the secondary reference glucose value. If, however, the
reference glucose values do not substantially correlate, it can be
presumed that the sensor glucose values are more accurate and the
reference glucose values eliminated from the algorithm.
FIG. 18 provides is a flow chart 250 that illustrates the
evaluation of calibrated sensor data for aberrant values in one
embodiment. Although sensor data are typically accurate and
reliable, it can be advantageous to perform a self-diagnostic check
of the calibrated sensor data prior to displaying the analyte data
on the user interface.
One reason for anomalies in calibrated sensor data includes
transient events, such as local ischemia at the implant site, which
can temporarily cause erroneous readings caused by insufficient
oxygen to react with the analyte. Accordingly, the flow chart 190
illustrates one self-diagnostic check that can be used to catch
erroneous data before displaying it to the user.
At block 252, a sensor data receiving module, also referred to as
the sensor data module, receives new sensor data from the
sensor.
At block 24, the sensor data transformation module continuously (or
intermittently) converts new sensor data into estimated analyte
values, also referred to as calibrated data.
At block 256, a self-diagnostic module compares the new calibrated
sensor data with previous calibrated sensor data, for example, the
most recent calibrated sensor data value. In comparing the new and
previous sensor data, a variety of parameters can be evaluated. In
one embodiment, the rate of change and/or acceleration (or
deceleration) of change of various analytes, which have known
physiological limits within the body, and sensor data can be
evaluated accordingly. For example, a limit can be set to determine
if the new sensor data is within a physiologically feasible range,
indicated by a rate of change from the previous data that is within
known physiological (and/or statistical) limits. Similarly, any
algorithm that predicts a future value of an analyte can be used to
predict and then compare an actual value to a time corresponding
predicted value to determine if the actual value falls within a
statistically and/or clinically acceptable range based on the
predictive algorithm, for example. In certain embodiments,
identifying a disparity between predicted and measured analyte data
can be used to identify a shift in signal baseline responsive to an
evaluated difference between the predicted data and
time-corresponding measured data. In some alternative embodiments,
a shift in signal baseline and/or sensitivity can be determined by
monitoring a change in the conversion function; namely, when a
conversion function is re-calculated using the equation y=mx+b, a
change in the values of m (sensitivity) or b (baseline) above a
pre-selected "normal" threshold, can be used to trigger a fail-safe
or further diagnostic evaluation.
Although the above-described self-diagnostics are generally
employed with calibrated sensor data, some alternative embodiments
are contemplated that check for aberrancy of consecutive sensor
values prior to sensor calibration, for example, on the raw data
stream and/or after filtering of the raw data stream. In certain
embodiments, an intermittent or continuous signal-to-noise
measurement can be evaluated to determine aberrancy of sensor data
responsive to a signal-to-noise ratio above a set threshold. In
certain embodiments, signal residuals (e.g., by comparing raw and
filtered data) can be intermittently or continuously analyzed for
noise above a set threshold. In certain embodiments, pattern
recognition can be used to identify noise associated with
physiological conditions, such as low oxygen (see, e.g., U.S.
Patent Publication No. US-2005-0043598-A1), or other known signal
aberrancies. Accordingly, in these embodiments, the system can be
configured, in response to aberrancies in the data stream, to
trigger signal estimation, adaptively filter the data stream
according to the aberrancy, or the like, as described in more
detail in the above cited co-pending U.S. Patent Publication No.
US-2005-0043598-A1.
In another embodiment, reference analyte values are processed to
determine a level of confidence, wherein reference analyte values
are compared to their time-corresponding calibrated sensor values
and evaluated for clinical or statistical accuracy. In yet another
alternative embodiment, new and previous reference analyte data are
compared in place of or in addition to sensor data. In general,
there exist known patterns and limitations of analyte values that
can be used to diagnose certain anomalies in raw or calibrated
sensor and/or reference analyte data.
Block 193 describes additional systems and methods that can by
utilized by the self-diagnostics module of the preferred
embodiments.
At decision block 258, the system determines whether the comparison
returned aberrant values. In one embodiment, the slope (rate of
change) between the new and previous sensor data is evaluated,
wherein values greater than +/-10, 15, 20, 25, or 30% or more
change and/or +/-2, 3, 4, 5, 6 or more mg/dL/min, more preferably
+/-4 mg/dL/min, rate of change are considered aberrant. In certain
embodiments, other known physiological parameters can be used to
determine aberrant values. However, a variety of comparisons and
limitations can be set.
At block 260, if the values are not found to be aberrant, the
sensor data transformation module continuously (or intermittently)
converts received new sensor data into estimated analyte values,
also referred to as calibrated data.
At block 262, if the values are found to be aberrant, the system
goes into a suspended mode, also referred to as fail-safe mode in
some embodiments, which is described in more detail below with
reference to FIG. 19. In general, suspended mode suspends display
of calibrated sensor data and/or insertion of matched data pairs
into the calibration set. Preferably, the system remains in
suspended mode until received sensor data is not found to be
aberrant. In certain embodiments, a time limit or threshold for
suspension is set, after which system and/or user interaction can
be required, for example, requesting additional reference analyte
data, replacement of the electronics unit, and/or reset.
In some alternative embodiments, in response to a positive
determination of aberrant value(s), the system can be configured to
estimate one or more glucose values for the time period during
which aberrant values exist. Signal estimation generally refers to
filtering, data smoothing, augmenting, projecting, and/or other
methods for estimating glucose values based on historical data, for
example. In one implementation of signal estimation,
physiologically feasible values are calculated based on the most
recent glucose data, and the aberrant values are replaced with the
closest physiologically feasible glucose values. See also U.S.
Patent Publication No. US-2005-0027463-A1, U.S. Patent Publication
No. US-2005-0043598-A1, and U.S. Patent Publication No.
US-2005-0203360-A1.
FIG. 19 provides a flow chart 280 that illustrates a
self-diagnostic of sensor data in one embodiment. Although
reference analyte values can useful for checking and calibrating
sensor data, self-diagnostic capabilities of the sensor provide for
a fail-safe for displaying sensor data with confidence and enable
minimal user interaction (for example, requiring reference analyte
values only as needed).
At block 282, a sensor data receiving module, also referred to as
the sensor data module, receives new sensor data from the
sensor.
At block 284, the sensor data transformation module continuously
(or intermittently) converts received new sensor data into
estimated analyte values, also referred to as calibrated data.
At block 286, a self-diagnostics module, also referred to as a
fail-safe module, performs one or more calculations to determine
the accuracy, reliability, and/or clinical acceptability of the
sensor data. Some examples of the self-diagnostics module are
described above, with reference block 256. The self-diagnostics
module can be further configured to run periodically (e.g.,
intermittently or in response to a trigger), for example, on raw
data, filtered data, calibrated data, predicted data, and the
like.
In certain embodiments, the self-diagnostics module evaluates an
amount of time since sensor insertion into the host, wherein a
threshold is set for the sensor's usable life, after which time
period the sensor is considered to be unreliable. In certain
embodiments, the self-diagnostics module counts the number of times
a failure or reset is required (for example, how many times the
system is forced into suspended or start-up mode), wherein a count
threshold is set for a predetermined time period, above which the
system is considered to be unreliable. In certain embodiments, the
self-diagnostics module compares newly received calibrated sensor
data with previously calibrated sensor data for aberrant values,
such as is described in more detail with reference to FIG. 5,
above. In certain embodiments, the self-diagnostics module
evaluates clinical acceptability, such as is described in more
detail with reference to FIG. 18, above. In certain embodiments,
diagnostics, such as are described in U.S. Pat. No. 7,081,195 and
U.S. Patent Publication No. US-2005-0143635-A1, can be incorporated
into the systems of preferred embodiments for system diagnosis, for
example, for identifying interfering species on the sensor signal
and for identifying drifts in baseline and sensitivity of the
sensor signal.
At block 288, a mode determination module, which can be a part of
the sensor evaluation module 224, determines in which mode the
sensor should be set (or remain). In some embodiments, the system
is programmed with three modes: 1) start-up mode; 2) normal mode;
and 3) suspended mode. Although three modes are described herein,
the preferred embodiments are limited to the number or types of
modes with which the system can be programmed. In some embodiments,
the system is defined as "in-cal" (in calibration) in normal mode;
otherwise, the system is defined as "out-of-cal` (out of
calibration) in start-up and suspended mode. The terms as used
herein are meant to describe the functionality and are not limiting
in their definitions.
Preferably, a start-up mode is provided, wherein the start-up mode
is set when the system determines that it can no longer remain in
suspended or normal mode (for example, due to problems detected by
the self-diagnostics module, such as described in more detail
above) and/or wherein the system is notified that a new sensor has
been inserted. Upon initialization of start-up mode, the system
ensures that any old matched data pairs and/or calibration
information is purged. In start-up mode, the system initializes the
calibration set, such as described in more detail with reference to
FIG. 13, above. Once the calibration set has been initialized,
sensor data is ready for conversion and the system is set to normal
mode.
Preferably, a normal mode is provided, wherein the normal mode is
set when the system is accurately and reliably converting sensor
data, for example, wherein clinical acceptability is positively
determined, aberrant values are negatively determined, and/or the
self-diagnostics modules confirms reliability of data. In normal
mode, the system continuously (or intermittently) converts
(calibrates) sensor data. Additionally, reference analyte values
received by the system are matched with sensor data points and
added to the calibration set.
In certain embodiments, the calibration set is limited to a
predetermined number of matched data pairs, after which the systems
purges old or less desirable matched data pairs when a new matched
data pair is added to the calibration set. Less desirable matched
data pairs can be determined by inclusion criteria, which include
one or more criteria that define a set of matched data pairs that
form a substantially optimal calibration set.
One inclusion criterion comprises ensuring the time stamp of the
matched data pairs (that make up the calibration set) span at least
a preselected time period (e.g., three hours). Another inclusion
criterion comprises ensuring that the time stamps of the matched
data pairs are not more than a preselected age (e.g., one week
old). Another inclusion criterion ensures that the matched pairs of
the calibration set have a substantially evenly distributed amount
of high and low raw sensor data points, estimated sensor analyte
values, and/or reference analyte values. Another criterion
comprises ensuring all raw sensor data, estimated sensor analyte
values, and/or reference analyte values are within a predetermined
range (e.g., 40 mg/dL to 400 mg/dL for glucose values). Another
criterion comprises evaluating the rate of change of the analyte
concentration (e.g., from sensor data) during the time stamp of the
matched pair(s). For example, sensor and reference data obtained
during the time when the analyte concentration is undergoing a slow
rate of change can be less susceptible to inaccuracies caused by
time lag and other physiological and non-physiological effects.
Another criterion comprises evaluating the congruence of respective
sensor and reference data in each matched data pair; the matched
pairs with the most congruence can be chosen. Another criterion
comprises evaluating physiological changes (e.g., low oxygen due to
a user's posture, position, or motion that can cause pressure on
the sensor and effect the function of a subcutaneously implantable
analyte sensor, or other effects such as described with reference
to FIG. 6) to ascertain a likelihood of error in the sensor value.
Evaluation of calibration set criteria can comprise evaluating one,
some, or all of the above described inclusion criteria. It is
contemplated that additional embodiments can comprise additional
inclusion criteria not explicitly described herein.
Unfortunately, some circumstances can exist wherein a system in
normal mode can be changed to start-up or suspended mode. In
general, the system is programmed to change to suspended mode when
a failure of clinical acceptability, aberrant value check and/or
other self-diagnostic evaluation is determined, such as described
in more detail above, and wherein the system requires further
processing to determine whether a system re-start is required
(e.g., start-up mode). In general, the system will change to
start-up mode when the system is unable to resolve itself in
suspended mode and/or when the system detects a new sensor has been
inserted (e.g., via system trigger or user input).
Preferably, a suspended mode is provided wherein the suspended mode
is set when a failure of clinical acceptability, aberrant value
check, and/or other self-diagnostic evaluation determines
unreliability of sensor data. In certain embodiments, the system
enters suspended mode when a predetermined time period passes
without receiving a reference analyte value. In suspended mode, the
calibration set is not updated with new matched data pairs, and
sensor data can optionally be converted, but not displayed on the
user interface. The system can be changed to normal mode upon
resolution of a problem (positive evaluation of sensor reliability
from the self-diagnostics module, for example). The system can be
changed to start-up mode when the system is unable to resolve
itself in suspended mode and/or when the system detects a new
sensor has been inserted (via system trigger or user input).
The systems of preferred embodiments, including a transcutaneous
analyte sensor, mounting unit, electronics unit, applicator, and
receiver for inserting the sensor, and measuring, processing, and
displaying sensor data, provide improved convenience and accuracy
because of their designed stability within the host's tissue with
minimum invasive trauma, while providing a discreet and reliable
data processing and display, thereby increasing overall host
comfort, confidence, safety, and convenience. Namely, the geometric
configuration, sizing, and material of the sensor of the preferred
embodiments enable the manufacture and use of an atraumatic device
for continuous measurement of analytes, in contrast to conventional
continuous glucose sensors available to persons with diabetes, for
example. Additionally, the sensor systems of preferred embodiments
provide a comfortable and reliable system for inserting a sensor
and measuring an analyte level for up to 7 days or more without
surgery. The sensor systems of the preferred embodiments are
designed for host comfort, with chemical and mechanical stability
that provides measurement accuracy. Furthermore, the mounting unit
is designed with a miniaturized and reusable electronics unit that
maintains a low profile during use. The usable life of the sensor
can be extended by incorporation of a bioactive agent into the
sensor that provides local release of an anti-inflammatory, for
example, in order to slow the subcutaneous foreign body response to
the sensor.
After the usable life of the sensor (for example, due to a
predetermined expiration, potential infection, or level of
inflammation), the host can remove the sensor and mounting from the
skin, and dispose of the sensor and mounting unit (preferably
saving the electronics unit for reuse). Another sensor system can
be inserted with the reusable electronics unit and thus provide
continuous sensor output for long periods of time.
EXAMPLES
FIG. 20A is a graphical representation showing transcutaneous
glucose sensor data and corresponding blood glucose values over
time in a human. The x-axis represents time, the first y-axis
represents current in picoAmps, and the second y-axis represents
blood glucose in mg/dL. As depicted on the legend, the small
diamond points represent the current measured from the working
electrode of a transcutaneous glucose sensor of a preferred
embodiment; while the larger points represent blood glucose values
of blood withdrawn from a finger stick and analyzed using an in
vitro self-monitoring blood glucose meter (SMBG).
A transcutaneous glucose sensor was built according to the
preferred embodiments and implanted in a human host where it
remained over a period of time. Namely, the sensor was built by
providing a platinum wire, vapor-depositing the platinum with
Parylene to form an insulating coating, helically winding a silver
wire around the insulated platinum wire (to form a "twisted pair"),
masking sections of the electroactive surface of the silver wire,
vapor-depositing Parylene on the twisted pair, chloridizing the
silver electrode to form silver chloride reference electrode, and
removing a radial window on the insulated platinum wire to expose a
circumferential electroactive working electrode surface area
thereon, this assembly also referred to as a "parylene-coated
twisted pair assembly."
An interference domain was formed on the parylene-coated twisted
pair assembly by dip coating in an interference domain solution (7
weight percent of a 50,000 molecular weight cellulose acetate
(Sigma-Aldrich, St. Louis, Mo.) in a 2:1 acetone/ethanol solvent
solution), followed by drying at room temperature for 3 minutes.
This interference domain solution dip coating step was repeated two
more times to form an interference domain comprised of 3 layers of
cellulose acetate on the assembly. The dip length (insertion depth)
was adjusted to ensure that the cellulose acetate covered from the
tip of the working electrode, over the exposed electroactive
working electrode window, to cover a distal portion of the exposed
electroactive reference electrode.
An enzyme domain was formed over the interference domain by
subsequently dip coating the assembly in an enzyme domain solution
and drying in a vacuum oven for 20 minutes at 50.degree. C. This
dip coating process was repeated once more to form an enzyme domain
having two layers. A resistance domain was formed over the
interference domain by subsequently spray coating the assembly with
a resistance domain solution and drying the assembly in a vacuum
oven for 60 minutes at 50.degree. C. Additionally, the sensors were
exposed to electron beam radiation at a dose of 25 kGy, while
others (control sensors) were not exposed to electron beam
radiation.
The graph illustrates approximately 3 days of data obtained by the
electronics unit operably connected to the sensor implanted in the
human host. Finger-prick blood samples were taken periodically and
glucose concentration measured by a blood glucose meter (SHBG). The
graphs show the subcutaneous sensor data obtained by the
transcutaneous glucose sensor tracking glucose concentration as it
rose and fell over time. The time-corresponding blood glucose
values show the correlation of the sensor data to the blood glucose
data, indicating appropriate tracking of glucose concentration over
time.
The raw data signal obtained from the sensor electronics has a
current measurement in the picoAmp range. Namely, for every unit
(mg/dL) of glucose, approximately 3.5 to 7.5 pA of current is
measured. Generally, the approximately 3.5 to 7.5 pA/mg/dL
sensitivity exhibited by the device can be attributed to a variety
of design factors, including resistance of the membrane system to
glucose, amount of enzyme in the membrane system, surface area of
the working electrode, and electronic circuitry design.
Accordingly, a current in the picoAmp range enables an analyte
sensor that: 1) requires (or utilizes) less enzyme (e.g., because
the membrane system is highly resistive and allows less glucose
through for reaction in the enzyme domain); 2) requires less oxygen
(e.g., because less reaction of glucose in the enzyme domain
requires less oxygen as a co-reactant) and therefore performs
better during transient ischemia of the subcutaneous tissue; and 3)
accurately measures glucose even in hypoglycemic ranges (e.g.,
because the electronic circuitry is able to measure very small
amounts of glucose (hydrogen peroxide at the working electrode)).
Advantageously, the analyte sensors of the preferred embodiments
exhibit improved performance over convention analyte sensors at
least in part because a current in the picoAmp range enables less
enzyme, less oxygen, better resolution, lower power usage, and
therefore better performance in the hypoglycemic range wherein
lower mg/dL values conventionally have yielded lower accuracy.
FIG. 20B is a graphical representation showing transcutaneous
glucose sensor data and corresponding blood glucose values over
time in a human. The x-axis represents time; the y-axis represents
glucose concentration in mg/dL. As depicted on the legend, the
small diamond points represent the calibrated glucose data measured
from a transcutaneous glucose sensor of a preferred embodiment;
while the larger points represent blood glucose values of blood
withdrawn from a finger stick and analyzed using an in vitro
self-monitoring blood glucose meter (SMBG). The calibrated glucose
data corresponds to the data of FIG. 20A shown in current, except
it has been calibrated using algorithms of the preferred
embodiments. Accordingly, accurate subcutaneous measurement of
glucose concentration has been measured and processed using the
systems and methods of the preferred embodiments.
FIG. 21 is a graphical representation showing transcutaneous
glucose sensor data and corresponding blood glucose values obtained
over approximately seven days in a human. The x-axis represents
time; the y-axis represents glucose concentration in mg/dL. As
depicted on the legend, the small diamond points represent the
calibrated glucose data measured from a transcutaneous glucose
sensor of a preferred embodiment; while the larger points represent
blood glucose values of blood withdrawn from a finger stick and
analyzed using an in vitro self-monitoring blood glucose meter
(SMBG). The calibrated glucose data corresponds to a sensor that
was implanted in a human for approximately seven days, showing an
extended functional life, as compare to three days, for
example.
Differentiation of Sensor Systems
Some embodiments provide sensor systems suitable for implantation
for 1 day, 3 days, 5 days, 7 days, or 10 days or more.
Alternatively, sensors designed for shorter or longer durations can
have one or more specific design features (e.g., membrane systems,
bioactive agent(s), architecture, electronic design, power source,
software, or the like) customized for the intended sensor life.
Similarly, some embodiments provide sensor systems suitable for a
variety of uses such as pediatrics, adults, geriatrics, persons
with type-1 diabetes, persons with type-2 diabetes, intensive care
(ICU), hospital use, home use, rugged wear, everyday wear,
exercise, and the like, wherein the sensor systems include
particular design features (e.g., membrane systems, bioactive
agent(s), architecture, electronic design, power source, software,
or the like) customized for an intended use. Accordingly, it can be
advantageous to differentiate sensor systems that are substantially
similar, for example, sensors wherein the electronics unit of a
sensor system can releasably mate with different mounting units, or
sensors wherein different electronics units designed for different
functionality can mate with a specific mounting unit.
In some embodiments, the mechanical, electrical, and/or software
design enables the differentiation (e.g., non-interchangeability)
of these different sensor systems. In other words, the sensor
systems can be "keyed" to ensure a proper match between an
electronics unit and a mounting unit (housing including sensor) as
described herein. The terms "key" and "keyed" as used herein are
broad terms and are used in their ordinary sense, including,
without limitation, to refer to systems and methods that control
the operable connection or operable communication between the
sensor, its associated electronics, the receiver, and/or its
associated electronics. The terms are broad enough to include
mechanical, electrical, and software "keys." For example, a
mechanically designed key can include a mechanical design that
allows an operable connection between two parts, for example, a
mating between the electronics unit and the mounting unit wherein
the contacts are keyed to mutually engage contacts of complementary
parts. As another example, an electronically designed key can
include a radio frequency identification chip (RFID chip) on the
mounting unit, wherein the electronics unit is programmed to
identify a predetermined identification number (key) from the RFID
chip prior to operable connection or communication between the
sensor and/or sensor electronics. As yet another example, a
software key can include a code or serial number that identifies a
sensor and/or electronics unit.
Accordingly, systems and methods are provided for measuring an
analyte in a host, including: a sensor configured for
transcutaneous insertion into a host's tissue; a housing adapted
for placement external to the host's tissue and for supporting the
sensor; and an electronics unit releasably attachable to said
housing, wherein at least one of the housing and the electronics
unit are keyed to provide a match between the sensor and the
electronics unit.
In some embodiments, the housing (including a sensor) and its
matching electronics unit(s) are keyed by a configuration of the
one or more contacts thereon. FIGS. 4A to 4C illustrate three
unique contact configurations, wherein the configurations are
differentiated by a distance between the first and second contacts
located within the housing. In this embodiment, a properly keyed
electronics unit is configured with contacts that mate with the
contacts on a mating housing (FIGS. 4A to 4C), for example a narrow
contact configuration on a housing mates only with a narrow contact
configuration on an electronics unit. Accordingly, in practice,
only an electronics unit comprising a contact configuration that is
designed for mutual engagement with a similarly "keyed" housing can
be operably connected thereto.
In some embodiments, the electronics unit is programmed with an ID,
hereinafter referred to as a "transmitter ID," that uniquely
identifies a sensor system. In one exemplary embodiment, wherein a
first sensor system is designed for 3-day use and a second sensor
system is designed for 7 day use, the transmitter ID can be
programmed to begin with a "3" or a "7" in order to differentiate
the sensor systems. In practice, a 3 day sensor system is
programmed for 3-day use (see enforcement of sensor expiration
described in more detail below), and thus upon operable connection
of a 3-day sensor system, the receiver can function for the
appropriate duration according to the transmitter ID.
In some embodiments, each sensor system is associated with a unique
or near-unique serial number, which is associated with one or a set
of sensor systems. This serial number can include information such
as intended duration, calibration information, and the like, so
that upon sensor insertion, and operable connection of the sensor
electronics, the serial number can be manually entered into the
receiver (from the packaging, for example) or can be automatically
transmitted from the sensor's electronics unit. In this way, the
serial number can provide the necessary information to enable the
sensor system to function for the intended duration.
Additionally or alternatively, the electronics unit and/or mounting
unit can be labeled or coded, for example, alpha-numerically,
pictorially, or colorfully, to differentiate unique sensor systems.
In this way, a user is less likely to confuse different sensor
systems.
Enforcement of Sensor Expiration (Duration of Sensor Life)
In general, transcutaneous sensor systems can be designed for a
predetermined life span (e.g., a few hours to a few days or more).
Some embodiments provide sensor systems suitable for 1 day, 3 days,
5 days, 7 days or 10 days or more. One potential problem that may
occur in practice is the continued use of the sensor beyond its
intended life; for example, a host may not remove the sensor after
its intended life and/or the host may detach and reattach the
electronics unit into the mounting unit (which may cause a refresh
of the sensor system and/or use beyond its intended life in some
circumstances). Accordingly, systems and methods are needed for
ensuring the sensor system is used for its proper duration and that
accidental or intentional efforts to improperly extend or reuse the
sensor system are avoided.
The preferred embodiments provide systems and methods for measuring
an analyte in a host, the system including: a sensor adapted for
transcutaneous insertion through the skin of a host; a housing
adapted for placement adjacent to the host's skin and for
supporting the sensor upon insertion through the skin; and an
electronics unit operably connected to the housing, wherein the
sensor system is configured to prevent use of the sensor (e.g., to
render the sensor inoperative) beyond a predetermined time
period.
In some embodiments, the sensor system is configured to destroy the
sensor when the electronics unit is removed and/or after a
predetermined time period has expired. In one exemplary embodiment,
a loop of material surrounds a portion of the sensor and is
configured to retract the sensor (from the host) when the
electronics unit is removed from the housing. In another
embodiment, the sensor system is configured to cut, crimp, or
otherwise destroy the sensor when the electronics unit is removed
from the housing.
In some embodiments, the sensor system is programmed to determine
whether to allow an initialization of a new sensor. For example,
the receiver can be programmed to require the sensor be
disconnected prior to initiation of the receiver for an additional
sensor system. In one such embodiment, the receiver can be
programmed to look for a zero from the electronics unit, indicating
the sensor has been disconnected, prior to allowing a new sensor to
be initiated. This can help to ensure that a user actually removes
the electronics unit (and/or sensor) prior to initialization of a
new sensor. In another such embodiment, sensor insertion
information can be programmed into the sensor electronics, such
that the sensor insertion information is transmitted to the
receiver to allow initialization of a new sensor.
In some embodiments, the receiver software receives information
from the electronics unit (e.g., intended duration, transmitter ID,
expiration date, serial code, manufacture date, or the like) and is
programmed to automatically shut down after a predetermined time
period (intended duration) or sensor expiration, for example.
In some embodiments, the receiver is programmed to algorithmically
identify a new sensor insertion by looking for change in signal
characteristic (e.g., a spike indicating break-in period, no change
in sensor count values during the first hour, or the like). If a
user has not inserted a new sensor, then the continued use of an
expired sensor can be detected and can be used to trigger a shut
down of the sensor and/or receiver.
In some embodiments, each sensor system is associated with a unique
or near-unique serial number, which is associated with one or a set
of sensor systems as described in more detail above. In general,
the serial number can include information such as calibration
information, intended duration, manufacture date, expiration date,
and the like. For example, the serial number can provide sensor
life (intended duration) information, which can be used to shut
down the sensor and/or receiver after the intended sensor life.
Laminate Sensor System Design
FIG. 22A is a perspective view of a sensor system including a
disposable thin laminate sensor housing in one embodiment. The
laminate sensor housing 400 includes an adhesive layer 408 and a
plurality of layers (see FIGS. 22B and 22C) beneath housing cover
454. The sensor housing 400 is adhered to the skin by the adhesive
layer 408, which is described in more detail elsewhere herein.
Preferably, the laminate housing is formed from a plurality of thin
layers secured together to form an overall thin housing.
In some embodiments, the overall height of the laminate housing is
preferably no more than about 0.5 inches in its smallest dimension,
more preferably no more than about 0.25 inches in its smallest
dimension, and most preferably no more than about 0.125 inches in
its smallest dimension. In some embodiments, the overall height of
the laminate housing is from about 0.075 inches or less, 0.080
inches or less, 0.090 inches or less, 0.100 inches or less, or
0.125 inches or less to about 0.150 inches or more, 0.200 inches or
more, 0.225 inches or more, or 0.250 inches or more; while the
length and/or width of the laminate housing can be substantially
greater, for example, at least about 0.25 inches or more, 0.5
inches or more, 1 inch or more or 1.5 inches or more. In some
embodiments, the aspect ratio of the laminate housing is at least
about 10:1, 15:1, 20:1, 30:1, 40:1, or 50:1.
FIGS. 22B and 22C are cut-away side cross-sectional views of the
thin, laminate, flexible sensor system in one embodiment. FIG. 22B
illustrates the laminate housing during sensor insertion in one
embodiment, wherein at least some of the layers are opened, peeled
and/or pivoted into an insertion position to allow insertion of the
sensor, after which the layers are folded, secured and/or pressed
down against the other of the layers in a manner such as described
in other embodiments described in more detail elsewhere herein. In
some alternative embodiments, however, the sensor can be inserted
through the layers without pivoting and/or opening of some of the
layers, after which a cover can be placed, for example. FIG. 22C
illustrates the laminate housing after sensor insertion in one
embodiment, wherein the layers are folded down and/or secured
together, and wherein the sensor and sensor electronics are
electrically connected. Although a particular order of layers is
illustrated in FIGS. 22B and 22C, one skilled in the art
appreciates that the layers can be repositioned relative to one
another, integrated with one another, and/or otherwise modified
while still enabling sensor function and performance.
In some embodiments, a sensor system is configured for measuring an
analyte in a host and generally includes a sensor 432 configured to
continuously measure an analyte concentration in a host and a
sensor housing 400 configured to receive the sensor. Preferably,
the sensor 432 is inserted through one or more layers of the
laminate housing and into the host's subcutaneous tissue using an
applicator such as those described in more detail elsewhere herein.
Suitable sensor configurations are also described in more detail
elsewhere herein.
Preferably, the sensor housing 400 is adapted for placement
adjacent to the host's skin and includes multiple layers (e.g., a
laminate housing) including one or more of the following functional
components: electronics operatively connected to the sensor 432 and
including a processor module configured to provide a signal
associated with the analyte concentration in the host, a power
source configured to power at least one of the sensor and the
electronics, an antenna configured for radiating or receiving an RF
transmission, and an adhesive layer configured to adhere the
housing to the host's skin. In some embodiments, the sensor housing
400 is a substantially planar, flexible, laminate housing.
Preferably, the sensor 432 is configured for insertion into the
host's tissue. Preferably, the system (e.g., sensor and sensor
housing) is configured for single-use (e.g., disposable). In some
embodiments, the sensor includes a first electrode and a second
electrode, wherein the first electrode includes a working
electrode, wherein the second electrode includes at least one of a
reference and counter electrode, and wherein the second electrode
is located on an adhesive layer (e.g., on the host's skin). In the
embodiment illustrated in FIG. 22B, the sensor is configured to
slide through an anti-stick material, also referred to as cannula
or cannula layer 460, wherein the anti-stick material is selected
such that the sensor can slide there through and/or such that the
laminate housing can be released there from; one exemplary material
suitable for use with the cannula layer is tetrafluoroethylene,
however one skilled in the art appreciates a variety of other
suitable anti-stick materials. During sensor insertion/deployment,
the sensor is configured to be received by and slide through the
cannula layer 460, after which the cannula layer is removed and a
seal is formed around the electrical contacts. In some embodiments,
some or the entire sensor is pre-inserted through the cannula
layer. Alternatively, an applicator can be provided to cooperate
with the cannula layer to enable sensor insertion there through. In
alternative embodiments, a cannula layer is not required.
In some embodiments, the sensor housing includes a power source
associated with (e.g., located in or on) a substantially planar,
flexible substrate. In some embodiments, the laminate sensor
housing 400 includes a flexible battery 444, which provides a
source of power for the sensor and/or electronics, as described in
more detail elsewhere herein. Although the battery 444 is shown as
a layer adjacent to the adhesive layer in the illustrated exemplary
embodiment, the flexible battery can be disposed in the adhesive
layer and/or laminated to the adhesive layer, including a
configuration wherein other layers are located between the flexible
battery and the adhesive layer. In some embodiments, the flexible
battery is no more than about 0.200, 0.100, 0.050, 0.030, 0.020, or
0.010 inches in its smallest dimension. In some embodiments, the
flexible battery is a thin, flexible battery and has an aspect
ratio of at least about 10:1. In some alternative embodiments, the
flexible battery is shaped to conform to at least a part of the
housing cover. In some embodiments, the battery is formed in a
spiral configuration. In some embodiments, the battery is combined
into another functional layer of the laminate housing; for example,
it may not be a distinct layer, per se.
In some embodiments, the laminate sensor housing 400 includes a
conductive contact layer 428, which provides an electrical
connection between the sensor 432 and sensor electronics (e.g.,
electrical contacts on the flexible circuit board 450). In some
embodiments, the conductive contact layer 428 forms at least a
portion of the electronics or electronics component. In some
embodiments, the conductive contact layer includes one or more
discrete electrical contacts configured to electrically connect one
or more electrodes of the sensor to the sensor electronics (e.g.,
deposited thereon, provided individually as described elsewhere
herein, or the like). In one exemplary embodiment wherein a cannula
layer is provided, the system is configured such that the
electrical contacts are held apart by the cannula layer, such that
removal of the cannula layer activates the electrical connection of
the sensor and electrical contacts.
Although the illustrated embodiments show the conductive contact
layer located between the battery and the flexible circuit board,
the conductive contact layer can be located in any location that
allows the layer to function as an electrical connector, including
as an integral part of the flexible circuit board (e.g., wherein
the conductive contact layer is a not distinct layer, per se.)
In some embodiments, the conductive contact layer 428 includes a
conductive material that only conducts in the z-axis. In one
exemplary embodiment, the conductive material is a z-axis
conductive film used to electrically connect the sensor to the
sensor electronics and includes an anisotropic conductor material,
for example, a film including anisotropic electrical conductivity,
i.e., z-axis conductivity, with little or no conductivity in the
other directions. In this exemplary embodiment, discrete electrical
contacts are not required, and instead, a piece of this anisotropic
conductor material to conduct multiple isolated signals (e.g., for
each electrode) is provided.
One example of a suitable Z-axis conductive film useful in
accordance with the some embodiments is a synthetic resin membrane
having nanometer-sized pores extending through the film from one
membrane surface to the other surface and having at least some of
its pores filled with a conductive material or composition, such as
gold or other metals, or with one or more nonmetallic conductive
materials. Preferably, the Z-axis conductive film has a thickness
of from about 0.0002 or less, 0.0003 inches, 0.0004 inches, or
0.0005 inches to about 0.0010 inches, 0.0025 inches, 0.0050 inches,
or 0.010 inches or more. The dimensions of the film and the metal
fibrils provide good performance at 50 GHz and higher frequencies.
U.S. Pat. No. 5,805,426, which is incorporated herein by reference
in its entirety, describes some z-axis conductive films suitable
for use in the preferred embodiments.
Another example of suitable z-axis electrical conductor films that
can be formed as adhesive and/or in standalone forms and can be
made from nickel particles (e.g., one per conduction path) and a
polymer matrix (e.g., polyvinylidene fluoride for the standalone
film and epoxy for the adhesive film), such as described in (see,
e.g., Yunsheng Xu and D. D. L. Chung, Journal of Electronic
Materials, Volume 28, Number 11, pp. 1307-1313 (1999), which is
incorporated herein be reference in its entirety).
In some embodiments, the sensor electronics are located on a
substantially planar, flexible substrate. In some embodiments, the
laminate sensor housing includes a flexible circuit board, such as
described in more detail elsewhere herein, on which at least a
portion of the sensor electronics are located. Preferably, the
flexible circuit board is at least one of disposed in the adhesive
layer, disposed on the adhesive layer, and laminated to the
adhesive layer, however other configurations are possible. In some
embodiments, the flexible circuit board is preferably no more than
about 0.200, 0.100, 0.050, 0.040, 0.030, 0.020 or 0.010 inches in
its smallest dimension. In some embodiments, the flexible circuit
board is combined into another functional layer of the laminate
housing; for example, it may not be a distinct layer, per se.
In some embodiments, the laminate sensor housing includes a housing
cover 454 configured and arranged to assist in and/or provide at
least one of water resistant, waterproof, and/or hermetically
sealed properties to the sensor housing; however, other portions
(e.g., layers) of the laminate housing can additionally include
configurations and arrangements that provide water resistant,
waterproof, and/or hermetically sealed properties. Additionally or
alternatively, the housing cover is configured to provide
mechanical and/or adhesive force for layers of the laminate
housing. Additionally or alternatively, the housing cover includes
an overcover-type bandage configured to cover some or all portions
of the sensor housing and/or adhesive of the device.
In some embodiments, the sensor housing includes an antenna
configured for radiating or receiving an RF transmission, wherein
the antenna is located on a substantially planar, flexible
substrate. In some embodiments, an antenna is at least one of
disposed in the adhesive layer, disposed on the adhesive layer, and
laminated to the adhesive layer, however other configurations are
possible. For example, the antenna can be located within any layer
of the laminate sensor housing. Alternatively, the sensor can be
configured to communicate with another device (e.g., a receiver)
using other communications systems and methods, including but not
limited to wired connectivity, IR, and the like. While not wishing
to be bound by theory, it is believed that a disposable thin
laminate sensor housing as described herein can reduce or eliminate
motion artifact caused by external influences (e.g., bumping or
other movement of the sensor housing), which in conventional sensor
systems (e.g., having sensor housing with lower aspect ratios
and/or greater thicknesses) is translated to the sensor in vivo,
causing motion artifact on the sensor signal. Accordingly, a more
stable signal with overall improved patient comfort can be achieved
with a thin laminate sensor housing as described herein.
The above described systems and methods for differentiating sensor
systems and enforcing sensor lifetimes can be used alone or in
combination, and can be combined with any of the preferred
embodiments.
Methods and devices that are suitable for use in conjunction with
aspects of the preferred embodiments are disclosed in U.S. Pat.
Nos. 4,994,167; 4,757,022; 6,001,067; 6,741,877; 6,702,857;
6,558,321; 6,931,327; 6,862,465; 7,074,307; 7,081,195; 7,108,778;
7,110,803; 7,192,450; 7,226,978; 7,236,890.
Methods and devices that are suitable for use in conjunction with
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Methods and devices that are suitable for use in conjunction with
aspects of the preferred embodiments are disclosed in U.S. patent
application Ser. No. 09/447,227 filed Nov. 22, 1999 and entitled
"DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS"; U.S. patent
application Ser. No. 11/675,063 filed Feb. 14, 2007 and entitled
"ANALYTE SENSOR"; U.S. patent application Ser. No. 11/543,396 filed
Oct. 4, 2006 and entitled "ANALYTE SENSOR"; U.S. patent application
Ser. No. 11/543,490 filed Oct. 4, 2006 and entitled "ANALYTE
SENSOR"; U.S. patent application Ser. No. 11/543,404 filed Oct. 4,
2006 and entitled "ANALYTE SENSOR"; U.S. patent application Ser.
No. 11/691,426 filed Mar. 26, 2007 and entitled "ANALYTE SENSOR";
U.S. patent application Ser. No. 11/691,432 filed Mar. 26, 2007 and
entitled "ANALYTE SENSOR"; U.S. patent application Ser. No.
11/691,424 filed Mar. 26, 2007 and entitled "ANALYTE SENSOR"; U.S.
patent application Ser. No. 11/691,466 filed Mar. 26, 2007 and
entitled "ANALYTE SENSOR"; U.S. patent application Ser. No.
11/692,154 filed Mar. 27, 2007 and entitled "DUAL ELECTRODE SYSTEM
FOR A CONTINUOUS ANALYTE SENSOR"; U.S. patent application Ser. No.
11/797,520 filed May 3, 2007 and entitled "TRANSCUTANEOUS ANALYTE
SENSOR"; U.S. patent application Ser. No. 11/797,521 filed May 3,
2007 and entitled "TRANSCUTANEOUS ANALYTE SENSOR"; and U.S. patent
application Ser. No. 11/750,907 filed May 18, 2007 and entitled
"ANALYTE SENSORS HAVING A SIGNAL-TO-NOISE RATIO SUBSTANTIALLY
UNAFFECTED BY NON-CONSTANT NOISE"; U.S. patent application Ser. No.
11/762,638 filed Jun. 13, 2007 and entitled "SYSTEMS AND METHODS
FOR REPLACING SIGNAL DATA ARTIFACTS IN A GLUCOSE SENSOR DATA
STREAM"; U.S. patent application Ser. No. 11/763,215 filed Jun. 14,
2007 and entitled "SILICONE COMPOSITION FOR BIOCOMPATIBLE
MEMBRANE"; U.S. patent application Ser. No. 11/842,148 filed Aug.
21, 2007 and entitled "TRANSCUTANEOUS ANALYTE SENSOR"; U.S. patent
application Ser. No. 11/842,142 filed Aug. 21, 2007 and entitled
"TRANSCUTANEOUS ANALYTE SENSOR"; U.S. patent application Ser. No.
11/842,154 filed Aug. 21, 2007 and entitled "TRANSCUTANEOUS ANALYTE
SENSOR"; U.S. patent application Ser. No. 11/842,146 filed Aug. 21,
2007 and entitled "ANALYTE SENSOR"; U.S. patent application Ser.
No. 11/842,151 filed Aug. 21, 2007 and entitled "ANALYTE SENSOR";
U.S. patent application Ser. No. 11/842,156 filed Aug. 21, 2007 and
entitled "ANALYTE SENSORS HAVING A SIGNAL-TO-NOISE RATIO
SUBSTANTIALLY UNAFFECTED BY NON-CONSTANT NOISE"; U.S. patent
application Ser. No. 11/842,157 filed Aug. 21, 2007 and entitled
"ANALYTE SENSOR"; U.S. patent application Ser. No. 11/842,143 filed
Aug. 21, 2007 and entitled "TRANSCUTANEOUS ANALYTE SENSOR"; and
U.S. patent application Ser. No. 11/842,149 filed Aug. 21, 2007 and
entitled "TRANSCUTANEOUS ANALYTE SENSOR".
All references cited herein, including but not limited to published
and unpublished applications, patents, and literature references,
are incorporated herein by reference in their entirety and are
hereby made a part of this specification. To the extent
publications and patents or patent applications incorporated by
reference contradict the disclosure contained in the specification,
the specification is intended to supersede and/or take precedence
over any such contradictory material.
All numbers expressing quantities of ingredients, reaction
conditions, and so forth used in the specification are to be
understood as being modified in all instances by the term "about."
Accordingly, unless indicated to the contrary, the numerical
parameters set forth herein are approximations that may vary
depending upon the desired properties sought to be obtained. At the
very least, and not as an attempt to limit the application of the
doctrine of equivalents to the scope of any claims in any
application claiming priority to the present application, each
numerical parameter should be construed in light of the number of
significant digits and ordinary rounding approaches.
The term "comprising" as used herein is synonymous with
"including," "containing," or "characterized by," and is inclusive
or open-ended and does not exclude additional, unrecited elements
or method steps.
The above description discloses several methods and materials of
the present invention. This invention is susceptible to
modifications in the methods and materials, as well as alterations
in the fabrication methods and equipment. Such modifications will
become apparent to those skilled in the art from a consideration of
this disclosure or practice of the invention disclosed herein.
Consequently, it is not intended that this invention be limited to
the specific embodiments disclosed herein, but that it cover all
modifications and alternatives coming within the true scope and
spirit of the invention.
* * * * *